CN1042532C - Novel compounds - Google Patents

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CN1042532C
CN1042532C CN93109874A CN93109874A CN1042532C CN 1042532 C CN1042532 C CN 1042532C CN 93109874 A CN93109874 A CN 93109874A CN 93109874 A CN93109874 A CN 93109874A CN 1042532 C CN1042532 C CN 1042532C
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phenyl
benzoxazolyl
methylamino
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CN1095716A (en
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D·赫格
J·T·塞姆
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SmithKline Beecham Ltd
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Priority claimed from GB929214185A external-priority patent/GB9214185D0/en
Priority claimed from GB929227030A external-priority patent/GB9227030D0/en
Priority claimed from GB939311027A external-priority patent/GB9311027D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

This invention provides compounds of formula (I):A1-X-(CH2)n-O-A2-A3-Y.R2(I)or a tautomeric form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein A1, A2, A3, R2, X, Y and n are as defined herein; pharmaceutical composition comprising such compounds and the use of such a compounds for treating hyperglycemia.

Description

Phenyl trifluoromethanesulfonate ethoxy-propionic acid that replaces and uses thereof
The present invention relates to some new compounds, prepare the method for this compounds, contain medicinal compositions and this compounds and the purposes of composition in medicine of this compounds.
The european patent application specification sheets, publication number is 0008203,0139421,0155845,0177353,0193256,0207581,0208420,0306228 and international patent application prospectus WO9101337 all relate to thiazolidine diketone derivative, they are considered to have hypoglycemic and fall blood ester activity.Chem. Pharm, Bull, 1982,30 (10) 3580-3600 relate to some to have hypoglycemic and falls the active thiazolidine diketone derivative of blood ester.
International patent application prospectus WO91/19702 discloses following formula (A) and compound (B): A is in the formula: Or
N is 0 or 1
M is 0,1 or 2;
Represent a chemical bond or do not have chemical bond;
R is (C 1-C 8) alkyl, (C 3-C 7) cycloalkyl, (C 3-C 8) alkenyl, (C 3-C 8) alkynyl, phenyl, (C 7-C 8) benzene alkyl, (C 2-C 8) alkanoyl, perhaps one of described group is by (C 1-C 3) alkyl, three fluoro-methyl, hydroxyl, (C 1-C 3) alkoxyl group, fluorine or chlorine list or two replacement;
W is O, CO, CH 2, CHOH or-CH=CH-;
X is S, O, NR 2,-CH=CH-,-CH=N-or-N=CH-;
R 2Be hydrogen, (C 1-C 3) alkyl, phenyl or benzyl;
Y is CH or N;
Z is H, amino, (C 1-C 7) alkyl, (C 3-C 7) cycloalkyl, phenyl or by (C 1-C 3) alkyl, trifluoromethyl, (C 1-C 3) alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy, fluorine or chlorine group list or disubstituted phenyl;
Z 1Be hydrogen or (C 1-C 3) alkyl;
X 1Be O, S, SO or SO 2And
Y 1Be hydroxyl, (C 1-C 3) alkoxyl group, phenoxy group, benzyloxy, amino, (C 1-C 4) alkyl amido, (C 1-C 4) alkane sulfuryl amino, phenylsulfonamido, naphthalene sulfonyl base amino, two [(C 1-C 3) alkyl] amino-sulfonyl amino, or be one of described group (C 1-C 3) alkyl, trifluoromethyl, hydroxyl, (C 1-C 3) alkoxyl group, fluorine or chlorine list replace or two replacement after group; Y wherein 1It is the medicinal cation salt of hydroxyl; And the medicinal acid addition salt that contains a basic nitrogen atom when compound.
The compound of chemical formula (A) has been considered to can be used as hypoglycemic medicament and hypocholesterolemia medicament.
People find some compounds uncannily now, are different from above-claimed cpd on its structure significantly, demonstrate fabulous hypoglycemic activity, thereby may be used for the treatment of and/or prevent hyperglycemia.Particularly can be used for treating type II diabetes.
These compounds have demonstrated the other diseases that may be used for the treatment of and/or prevent to comprise high blood ester disease and essential hypertension, and they also demonstrate and can be used for treating and/or preventing cardiovascular disorder, particularly atherosclerosis.In addition, these compounds also are considered to can be used for treating some eating disorder disease, are particularly useful for the adjustment that needs appetite and food intake owing to disorderly, and these disorders comprise to be owed to eat, as anorexia nervosa; The overfeeding disorders is as obesity and exessive appetite.
Usually, the invention provides a kind of compound of formula I:
A 1-X-(CH 2) n-O-A 2-A 3-YR 2(I) or its isomeric forms and/or its a kind of pharmaceutical salts, with and/or its medicinal solvent thing, wherein:
A 1Represent one to replace or unsubstituted heteroaromatic group;
A 2Represent one to have optional three substituent phenyl ring;
A 3Represent chemical formula to be-(CH 2) m-CH (OR 1) part, R wherein 1Replace or the unsubstituted alkyl of expression, aryl, aralkyl or alkyl carbonyl and m represents an integer of 1 to 5, or A 3The expression chemical formula is-(CH 2) M-1-CH=C (COR 1)-, and wherein R 1Define as above with m;
R 2Expression OR 3, R wherein 3Be hydrogen, alkyl, aryl or aralkyl; Or R 2Represent a heteroaromatic group or-NR 4R 5, R wherein 4And R 5Hydrogen, alkyl or alkyl-carbonyl, perhaps R respectively do for oneself 4And R 5Together be connected to and form a heterocycle on the nitrogen-atoms, condition is that Y shows a chemical bond, R as following definition list 2Represent a heteroaromatic group; X represents NR, and wherein R is hydrogen atom, alkyl, acyl group, aryl moiety can be substituted or unsubstituted aralkyl, or replacement or unsubstituted aryl; Y represents C=O or C=S or valence bond, and condition is only to work as R 2When expression as above-mentioned heteroaromatic group, Y just represents a valence bond; N represents an integer of 2-6 scope again.
Suitable heteroaromatic group comprises and replacing or unsubstituted, single or condensed ring heteroaromatic group, wherein contains four heteroatomss that are selected from oxygen, sulphur or nitrogen at the most on each ring.
Preferred heteroaromatic group comprises and replacing or unsubstituted 5 to 7 annular atomses, preferably the monocycle heteroaromatic group of 5 or 6 annular atomses of containing.
Further, heteroaromatic group contains 1,2 and 3 heteroatoms, and particularly 1 or 2 is selected from oxygen, sulphur or nitrogen.
Work as A 1When representing five yuan of heteroaromatic group, suitable A 1Comprise thiazolyl with oxazolyl, Te other Shi oxazolyl.
Work as A 1When representing a hexa-atomic heteroaromatic group, suitable A 1Group comprises pyridyl, pyrimidyl, especially pyridyl.
A preferably 1The expression chemical formula is (a) and (b) or part (c)
Figure C9310987400061
In the formula: R 6And R 7Represent hydrogen or halogen atom, an alkyl or an alkoxyl group or a replacement or unsubstituted aryl separately; Perhaps work as R 6And R 7Be connected to separately on the adjacent carbons, then R 6And R 7Coupled together carbon atom forms a phenyl ring, wherein by R 6And R 7The carbon atom of representative can replace or not be substituted; In the part of formula (a), X 1Expression oxygen or sulphur.
Exactly, A 1A part of representing the formula (a) of above-mentioned definition.
Exactly, A 1A part of representing the formula (b) of above-mentioned definition.
Exactly, A 1A part of representing the formula (c) of above-mentioned definition.
(c) Bu Fen a kind of particular form is (c ＇) part;
Figure C9310987400071
R in the formula 6And R 7Identical as the definition in formula (c).
In a kind of preferred mode, R 6And R 7Represent the part of formula (d) altogether:
Figure C9310987400072
R in the formula 8aAnd R 8bIndependent separately expression hydrogen, halogen, replacement or unsubstituted alkyl or alkoxyl group.
That suitable is R 8aAnd R 8bRepresent hydrogen, halogen, alkyl or alkoxyl group, R preferably separately 8aRepresent hydrogen.R preferably 8bRepresent hydrogen.R preferably 8aAnd R 8bAll represent hydrogen.
In a kind of more preferred mode, R 6And R 7Represent separately that hydrogen, alkyl or one replace or unsubstituted phenyl, R preferably 6And R 7Represent hydrogen, alkyl or phenyl separately.
Preferably, for formula (a) part, R 6And R 7Expression (d) part altogether.
Preferably, for the part of formula (b), (c) or (c ＇), R 6And R 7All represent hydrogen.
For A 2Optional substituting group can be selected from halogen, replacement or unsubstituted alkyl and alkoxyl group.
Preferably, A 2The part of expression (e):
Figure C9310987400081
R in the formula 10And R 11Represent separately hydrogen, halogen, replacement or unsubstituted alkyl or alkoxyl group.
That suitable is R 10And R 11Represent hydrogen, halogen, alkyl or alkoxyl group independently of one another.
Work as R 10And R 11During representation alkoxy, a suitable alkoxyl group is a methoxyl group.
R preferably 10And R 11Each represents hydrogen.
That suitable is A 3The expression structural formula is-(CH 2) m-CH (OR 1)-part.
That suitable is A 3The expression structural formula is-CH=(OR 1)-part.
Work as R 1When representing alkyl, suitable alkyl is C 1-6Alkyl, for example methyl, ethyl, propyl group (such as n-propyl and sec.-propyl) and butyl are as the tertiary butyl.Preferred alkyl is an ethyl.
Work as R 1When being substituted alkyl, for the specified substituent of this alkyl comprise halogen, hydroxyl, alkoxyl group or-NR sR tPart, wherein R sAnd R tIndependent separately expression hydrogen or alkyl; Or R sAnd R tCommon coupled nitrogen-atoms forms-5 yuan or 6 yuan of heterocycles together, or by formula-COX 2The part of expression, wherein X 2Expression OH, the formula-NR of alkoxyl group or above-mentioned definition sR tPart.
Suitable alkylhalide group comprises fluoroalkyl, for example three fluoro ethyls.
Usually work as R 1When being monobasic alkyl, this substituting group is to be connected on the terminal carbon atom of this alkyl.
Work as R 1When representing alkyl carbonyl, suitable alkyl carbonyl comprises C 1-6Alkyl carbonyl.
Work as R 1When being aryl, suitable aryl comprises phenyl or naphthyl.
Work as R 1When representing aralkyl, suitable aralkyl comprises the benzene alkyl, as benzyl and styroyl.
Preferred aralkyl is a benzyl.
For by R 1The preferred substituents of the aryl of representative comprises halogen, alkyl or alkoxyl group; The substituent example of this class comprises chloro, methyl and methoxyl group.
That suitable is R 1Representative that replace or unsubstituted alkyl or replacement or unsubstituted aralkyl.
R preferably 1Be alkyl or the unsubstituted aralkyl that replaces.
R 2Be expression OR aptly 3
R 3Be the expression hydrogen or alkyl aptly.
Work as R 3When being alkyl, R 3Example comprise methyl and ethyl.
Work as R 2When being a heteroaromatic group, what it was suitable is the monocycle heteroaromatic group with 5 yuan of annular atomses, and annular atoms wherein contains nitrogen and 1,2 or 3 optional other heteroatoms; Comprise 1,2 for example, the 4-triazole; 1,2,4-oxadiazole and tetrazyl; Usually this heteroaromatic group is the C-chain.
Suitable substituting group on fragrant heterocycle is an alkyl, aryl, alkoxyl group and halogen, and the suitable example that replaces is a methyl.
When-NR 4R 5Or-NR sR tWhen representing a heterocyclic radical, preferred heterocycle is saturated or undersaturated, fused heterocycle or single heterocycle, on each ring, contain 5,6 or 7 annular atomses and contain in addition 1 or 2 other be selected from the heteroatoms of OS or N.Preferred ring is a saturated rings.Preferred ring is a unit loop.Preferred other heteroatoms is N or O.The example of the assorted unit of this class ring comprises N-pyrrolidyl, N-piperidyl and N-morpholinyl.
NR 4R 5Another example be NH 2
That suitable is R 2Expression NR 4R 5
R 2OR preferably 3
Suitable is to work as R 2Represent OR 3(R wherein 3Expression hydrogen, alkyl, aryl or aralkyl) or R 2Representative-NR 4R 5The time, Y is CO or CS; Preferred Y is CO.
Work as R 2When being fragrant heterocycle, Y is a chemical bond.
Suitable is that R represents hydrogen or alkyl.
When R was acyl group, suitable acyl group comprised alkyl carbonyl, as ethanoyl.
Suitable is that m represents 1 or 2.
M preferably 1.
N preferably 2.
As above-mentioned, the compound of formula I and its medicinal salts one of can several tautomeric forms exist, and these are with alone tautomeric forms or all belonging within the scope of the present invention with its form of mixtures.The compound of formula I can contain at least one chiral carbon atom, thereby the form that they can one or more steric isomers exists.For example work as R 3Represent a chemical formula to be-(CH 2) m-CH (OR 1)-part the time, CH (OR then 1)-atom is a chiral carbon, in addition, when A5 represents a structural formula is-(CH 2) M-1-CH=C (OR 1)-part the time, the compound of formula I exists with the form of geometrical isomer.No matter the present invention includes the form of all isomer of formula I compound and its pharmaceutical salts, be independently isomer or its mixed isomers, comprises racemoid.
Suitable substituting group for heterocyclic group comprises can reach four substituting groups, these substituting groups are selected from: the carbon atom that alkyl, alkoxyl group, aryl or halogen or any two substituting groups on adjacent carbons can be coupled forms aryl together, phenylene preferably, and the carbon atom on the aryl of being represented by described two substituting groups self can be that replace or unsubstituted.
In herein, unless specialize, term " aryl " comprises phenyl and naphthyl, the mentioned aryl of this paper all can be at random by maximum five, preferably 3 groups that are selected from following groups replace, and these groups are halogen, alkyl, phenyl, alkoxyl group, haloalkyl, hydroxyl, amino, nitro, carboxyl, carbalkoxy, alkoxycarbonyl alkyl, alkyl carbonyl oxygen or alkyl carbonyl.
Term used herein " halogen " is meant fluorine, chlorine, bromine and iodine, preferably chlorine.
In herein, alkyl is an Individual existence or all be the alkyl with straight or branched as the part (as alkoxyl group or aralkyl) of other group, can contain 12 carbon atoms at most.Thereby suitable alkyl is C 1-12Alkyl, particularly C 1-6Alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.
Suitable substituting group on the alkyl comprises those groups that those are pointed out in term " aryl ".
Preferred aralkyl is the benzene alkyl, and aryl that can at random define hereinafter or moieties replace.
Suitable acyl group comprises alkyl carbonyl.
Suitable pharmaceutical salts comprises carboxylate radical salt and acid addition salt.
The pharmaceutical salts of suitable carboxylate radical comprises metal-salt, aluminium for example, an alkali metal salt such as lithium, sodium or potassium, alkaline earth salt such as calcium or magnesium and ammonium or substituted ammonium salt, for example those have low alkyl group amine such as triethylamine, hydroxyalkyl amine such as 2 hydroxy ethylamine, two (2-hydroxyethyl) amine or three (2-hydroxyethyl) amine, or three (2-hydroxyethyl) amine, Cycloalkyl amine such as dicyclohexyl amine, or those have PROCAINE HCL, PHARMA GRADE, the dibenzyl piperidines, N-benzyl-β-phenylethylamine, dehydroabietylamine, N, N ＇-two dehydroabietylamines, glycosamine, N-methylglucosamine or pyridine type alkali such as pyridine, collidine, the ammonia salt of quinine or quinoline.
Suitable acid addition salt comprises medicinal inorganic salt, as vitriol, nitrate, phosphoric acid salt, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid additive salt such as acetate, tartrate, maleate, lemon rubber hydrochlorate, succinate, benzoate, ascorbate salt, mesylate, alpha-ketoglutarate and α-glycerophosphate.
Suitable medicinal solvent thing comprises hydrate.
The salt of formula I compound and/or solvate can prepare according to the method for routine or separate, and can be dissolved in the methyl alcohol by the methoxide with sodium as sodium salt preparing.
On the other hand, the present invention also provides a kind of compound for preparing chemical formula I, or its tautomeric forms, and/or its medicinal salts, and/or the method for its hydrate for medicinal use, this method comprises that the compound of formula II is with the same suitable reagent reaction of the compound of formula II
R a-A 2-A 3＇-Y.R 2＇
(Ⅱ)
A in the formula 2With Y as the definition in formula I;
A 3 ＇Represent a structural formula to be-(CH 2) m-CH (OR 1 ＇)-part, R wherein 1 'Representative as the R that in formula I, defines 1Or the form of its a kind of protection, and m is as the definition in formula I, or A 3Represent that a structural formula is-(CH 2) M-1-CH=C (OR 11)-part, wherein R 1 'As above-mentioned definition; R 2 ＇Representative is as the R that defines in formula I 2Or its protection form, R aBe a part that can change an accepted way of doing sth (f):
A 1-X-(CH 2) A in n-O-(f) formula 1, X and n be as the definition in formula I; And this suitable reagent is can be with R aBe transformed into described (f) part, and, can carry out one or more following optional step as needs:
(ⅰ) a kind of compound of formula I is transformed into the compound of another kind of formula I;
(ⅱ) protecting group of any necessity of removal;
(ⅲ) pharmaceutical salts and/or its medicinal solvent thing of preparation formula I compound;
Aptly, R aRepresent HX-(CH 2) n-O-, wherein X and n be as the definition in formula I, or R aRepresent OH.
R preferably aRepresent OH.
Work as R aBe HX-(CH 2) n-O-, a kind of can be with R aThe suitable reagent that is transformed into (f) part is the compound of formula III:
A 1-R xA in (III) formula 1As the definition in the formula I, R again xRepresent a leaving group.
Suitable leavings group R xComprise halogen atom, chlorine or bromine atom preferably, or alkylthio such as sulphomethyl.
Usually, R 1 'Be R 1, preferred R 2 ＇Represent OR 3 ＇, R wherein 3 ＇Represent hydrogen, alkyl, aryl, aralkyl or R 2 ＇Represent the part-NR of above-mentioned definition 4R 5
Work as R aWhen being OH, suitable reaction reagent be formula (III compound a):
A 1-X-(CH 2) n-OR yA in (III A) formula 1, x and n be as the definition in formula I, R yRepresent a leaving group, as toluene, sulfonate group or methylsulfonic acid ester group.
The compound of formula II and should suitable reagent between chemical reaction can carry out under specific formula I compound and the selected reagent condition being suitable for: the compound of formula II above-mentioned (R wherein for example aRepresent HX-(CH 2) n-O-) and the formula III compound between reaction can in any suitable solvent, carry out, dimethyl formamide for example, be under the temperature of the formation speed that can guarantee suitable formula I compound, for example, preferably exist under a kind of alkali such as the triethylamine condition and carry out at 50 ℃-120 ℃ high temperature range.
In another example, R wherein aBe that reaction between formula (III A) reaction reagent of the compound of formula II of OH and above-mentioned definition can be in a kind of aprotic solvent, as dimethyl formamide, warm from low to high, as in 50 ℃ to 120 ℃ scopes, carrying out, as at 80 ℃ and be preferably in the presence of a kind of alkali, react as under the sodium hydride, in another kind of alternative plan, the R in chemical formula (III A) YExpression H and R aWhen being OH in formula II, then suitable reagent can be azoethane dicarboxylic ester and triphenylphosphine; This coupled reaction can be in to hang down in The suitable solvent carries out under medium temperature condition, carries out as being in tetrahydrofuran (THF) under 0-60 ℃.
The compound of formula II, wherein A 3 ＇Representative-(CH 2) m-CH (OR 1 ＇)-part can prepare by a kind of carbene thing of formula IV is reacted with the compound of a kind of formula (V), and the chemical formula of formula IV is:
R b-A 2-(CH 2) m-C-Y-R 9A in (IV) formula 2, the definition in Y and m and the formula I compound identical, R bBe R aThe part or can be transformed into R aPart, and R 9Be the R of above-mentioned definition 2 ＇An or protecting group; The compound of formula (V) is:
R 1 ＇R in OH (V) formula 1 ＇As the definition in formula II; Then, if desired, then with R bBe transformed into R aPart removes protecting group then.
Preferably Y is CO, preferred R 9Be OR 3 ＇Or-NR 4R 5The suitable source of the carbene thing of chemistry formula IV is the compound with formula (IV A): (A in the formula 2, R 9, R 6, Y is identical with what define in the formula IV with m) with a kind of rhodium (II) salt, react as rhodium acetate.
The condition of the carbene thing of preparation formula IV depends on selected particular carbon alkylene thing certainly from (IV A).But used condition in general ordinary method, as being that carbene and (IV A) are the carbene sources when (IV), so Shi Yi condition is to be similar at Tetrahedron, Lett, disclosed condition in 1973,2233.
Reaction between the carbene of formula IV and formula (V) compound can be carried out under the condition of routine, usually in a kind of inert solvent, as in compound (V), making solvent in benzene or the practicality, be under the temperature of any production rate that guarantees suitable required product, for example the reflux temperature of solvent.Suitable is that used condition is similar at TetrahedronLett, disclosed condition in 1973,2,233 one literary compositions.
When this carbene source was formula (IV A) compound, formula (IV A) compound can prepare by the compound of formula VI and a suitable diazotization agent are carried out diazotization reaction, and formula VI is: A in the formula 2, R 9, R b, Y and m be identical with the compound definition of formula IV; After this, as needs, can be with R bPart changes into R a, and can remove any protecting group.
One suitable diazotization agent is an alkyl nitrite, as Isopentyl nitrite.
The diazotization condition of preparation formula (IV A) compound is a normal condition, for example is disclosed in Tetrahedron Lett., those conditions in 1971,4495.
Any R bPart all can change into R by suitable traditional method aPart, as work as R bRepresentative-OH and R aRepresent HX-(CH 2) n-O-, then Shi Yi conversion can be by with the compound of formula VI (R wherein bBeing OH) compound of cotype (g) carries out coupled reaction and carries out, and formula (g) is:
R 2-X-(CH 2) define R in X and n such as the formula I in n-OH (g) formula 2Be a protecting group, then, if necessary, removable blocking group.
Last above-mentioned reaction is carried out having under the suitable coupling agent condition usually; Suitable coupling agent is azoethane dicarboxylic ester and triphenylphosphine, and this coupled reaction is in to hang down usually in The suitable solvent carries out under medium temperature condition, as carrying out 0-60 ℃ of scope at tetrahydrofuran (THF) and temperature.
Usually, for by formula IV compound (II) compound, R in the formula aBe OH, the R in the formula IV then bOr OH or protected OH, as henzylate OH.
The compound of formula (V) is the known commercially available compound that gets, and perhaps the similar approach of their available this compounds of preparation prepares it.
The formula VI compound is a known compound, or they can prepare by the similar approach that adopts the preparation known compound, as is disclosed in Tetrahedron Lett., method in 1971,4,495 one literary compositions, especially this compound, i.e. R 9Be OCH 3, m is 1, A 2Be 1,4-phenylene and R bThe compound that is OH is commercially available.
The compound of formula (g) is a known compound, or they can prepare as disclosed method in EP0356214 by the similar approach of preparation known compound:
A kind of compound of formula I [A in the formula 5Representative (CH 2) m-CH (OR 1) part], or its tautomeric forms, and/or a kind of pharmaceutical salts and/or its medicinal solvent thing all can prepare by formula (VII) compound of activated form and formula (VIII) compound are reacted; Formula (VII) is:
Figure C9310987400171
A in the formula 1, A 2, identical in X, Y, m and n and the formula II, R 9Identical with definition in the formula IV; Formula (VIII) is:
R 1-L 1R in (VIII) formula 1Identical with definition in the formula I, L 1Represent a leaving group or atom; Can carry out a step or the following step of multistep then if desired:
(ⅰ) a kind of formula I compound is changed into the compound of another kind of formula I;
(ⅱ) remove any protecting group; With
(ⅲ) a kind of pharmaceutical salts and/or its medicinal solvent thing of preparation formula I compound:
Suitable is L 1Be a halogen atom, as bromine atoms.
A kind of suitable activity form of formula (VII) compound is a kind of anionic form, for example with a kind of form of salinization, particularly with basic metal salinization form, as sodium salt.
The activity form of formula (VII) compound can adopt the preparation of any suitable ordinary method, for example the anionic form of formula (VII) compound can by with the compound of (VII) with a kind of alkali, such as metal hydride alkali, for example sodium hydride reacts and prepares.
Reaction conditions for the reaction between formula (VII) and (VIII) compound is common conventional alkylation conditions, reaction between the formula of for example salinization form (VII) compound and formula (VIII) compound can be carried out in a kind of aprotonic solvent such as dimethyl formamide, as long as temperature of reaction of living in guarantees desired product suitable formation speed is arranged, normally at high temperature, in 40 ℃ to 100 ℃ scopes, under 80 ℃, carry out.
Preferably, form the activity form of (VII) by formula (VII), the salinization form that for example forms (VII) can be carried out before (VII) of activity form reacted with formula (VII) compound of above-mentioned definition on the spot.
The preparation of the compound of formula (VII) can react the compound of formula (IX) and obtain with a kind of suitable reagent. and the compound of formula (IX) is: R in the formula a, R 9, A 2, the definition of Y and m such as above-mentioned, T is hydrogen or hydroxyl protecting group; This suitable reagent is can be with R aChange into the part of the formula (f) of above-mentioned definition.
Can be with R aThe reagent of a conversion accepted way of doing sth (f) part identical as what from the formula II compound, define during formation formula I compound above-mentioned definition relevant.
Suitable R aGroup is identical with above-mentioned definition.
Condition when the conditions suitable that reacts for compound and suitable reagent with formula (IX) comprises the described suitable reagent preparation formula II compound of those usefulness in last narration.
Preferably, in formula (IX) compound, R aRepresent a hydroxyl, and special suitable reagent is formula (III A) compound of above-mentioned definition.
Compound (IX) (R wherein aBe monohydroxy) and formula (III A) reagent of above-mentioned definition between reaction can be in a kind of aprotonic solvent (as dimethyl formamide), warm from low to high, for example in 50 ℃ to 120 ℃ temperature ranges, such as under 80 ℃, reacting, preferably there is a kind of alkali, as carrying out under the sodium hydride condition.
Compound (the R in the formula of formula (IX) aBe OH), be compound known or by being similar to the compound of the method preparation that is used for preparing known compound.For example, be disclosed in Dictionary of Organic Compounds 5th Edition, Vol.3, P.3222, Chapman δ Hall, or people J.Chem.Soc such as D.H.Williams, section B, 1969,439, or J.Maroh, Advanced Orgni c Chemistry, 3rdEdition (1985), Wiley Interscienece or be disclosed in International, Application, the method among the publication No.Wo92/02520.
The compound of formula I (A in the formula 3Expression-(CH 2) m-CH (OR 1 ')-partly), or its isomeric form, but and/or its pharmaceutical salts and/or its medicinal solvent thing also the compound of the source of through type (X) carbene and top definite formula (V) react and prepare: A 1-X-(CH 2) n-O-A 2-(CH 2) m-C-Y-R 9A in (X) formula 1, A 2, X, Y, m and n define same formula I, R 9Define same formula IV; If desired, after this carry out one or several following arbitrary step:
(ⅰ) the formula I compound is transformed into the compound of other formula I;
(ⅱ) remove arbitrary protecting group and
(ⅲ) pharmaceutical salts and/or its medicinal solvent thing of preparation formula I compound.
It is to make formula (XI) compound and rhodium (II) salt that suitable formula (X) carbene source is provided, and reacts as rhodium acetate (II):
Figure C9310987400191
A in the formula 1, A 2, R 9, X, Y, m and n definition cotype (X).
Formula (X) carbene can be similar to the processing method of being used by formula (IV A) compound chemistry formula IV carbene by use by formula (XI) compound and prepare.
The condition that the reaction conditions that reacts between chemical formula (X) and (V) compound uses with reaction between chemical formula IV and (V) compound.
The compound of preparation chemical formula (XI) can pass through the reaction between chemical formula (III A) and (VI) compound, the processing method of using is similar to the processing method of being used by chemical formula II and (III A) compound chemistry formula I compound, after this carries out diazotization as mentioned above for making (IV) be transformed into (IV A).Compound (the A in the formula of chemistry formula I 3Expression chemical formula-(CH 2) M-1-CH=C (OR 1)-or-(CH 2) m-CH (OR 1)-partly), or its isomeric forms, and/or its pharmaceutical salts and/or its medicinal solvent thing also can be by chemical formula (XII) compound and the chemical formula CH=C (OR that the CHO carbon atom is determined above being transformed into 1)-Y-R 2The reagent react of base prepares:
A 1-X-(CH 2) n-O-A 2-(CH 2) M-1A in-CHO (XII) formula 1, A 2, X, m and n definition is with chemical formula I; If desired, reduction-CH=C (OR after this 1)-Ji is to provide wherein A 3Expression chemical formula-(CH 2) m-CHOR 1The compound of-part; If desired, after this carry out one or several following any step:
(ⅰ) make chemical formula I compound be transformed into other chemical formula I compound;
(ⅱ) remove any protecting group; With
(ⅲ) pharmaceutical salts and/or its medicinal solvent thing of the chemical formula I compound of preparation.
The suitable CHO carbon atom that can make is transformed into the top chemical formula-CH=C (OR that determines 1)-Y.R 2The reagent of base is the Witttig reagent or the Wadsworth Emmons reagent of chemical formula (X III) preferably:
Figure C9310987400211
R in the formula 1 ＇, R 2 ＇Define with chemical formula II, R with Y 10Expression C 1-6Alkyl, preferably methyl or ethyl.
Reaction between chemical formula (XII) and (the X III) can be carried out under common Wadsworth Emmons reaction conditions, for example in aprotonic solvent (as tetrahydrofuran (THF)), arrive under the temperature (as 0-25 ℃ of scope) of room temperature at low temperature, suitable is at room temperature, preferably carries out under inert atmosphere He under the anhydrous condition.Preferably chemical formula (X III) compound is suitably activated, for example by before adding chemical formula (XII) compound, adding alkali, as sodium hydride or positive fourth lithium.
Reducing compound (A wherein 5Expression chemical formula-(CH 2) M-1-CH=C (OR 1)-part) so that compound (A wherein to be provided 3Expression chemical formula-(CH 2) m-CH (OR 1)-partly (can use common method of reducing to carry out, for example use as 10% carbon-containing palladium catalyst catalytic reduction in alkanol solvent (as ethanol), or by using metal/solvent system, as MAGNESIUM METAL/methyl alcohol, as Tet.Lett.1986 is described in 27,2409.
Chemical formula (XII) compound can be by chemical formula (XII A) compound:
A 1-X-(CH 2) n-O-A 2-(CH 2) M-1-CO 2R aA in (XII A) formula 1, A 2, X, m and n definition is with chemical formula I: R aExpression hydrogen or C 1-6Alkyl, suitable is methyl, by general method ester group is transformed into carbonyl prepares; A kind of appropriate means comprises to be used as metal hydride reducing agent (as lithium aluminum hydride) reduce ester group and produces primary alconol in tetrahydrofuran (THF), after this by use oxygenant (as pyridine-sulphur trioxide title complex) in methyl-sulphoxide, make primary alconol oxidation generation need carbonyl.
Chemical formula (XII A) compound can be prepared by chemical formula (XII B) compound and the chemical formula of stipulating above (III A) compound:
HO-A 2-(CH 2) M-1-CO 2R aA in (XII B) formula 2, m and R aDefine same chemical formula (XII A).
The as above described condition of reaction between surface chemistry formula II t and (III A) compound of appropriate reaction conditions between chemical formula (III A) and (XII B) compound.
Chemistry formula II compound (A wherein 3 ＇Expression chemical formula-CH=C (OR 1 ＇-or-CH 2-CH (OR 1 ＇) part) or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing can be by making chemical formula (X IV) compound and chemical formula-CH=C (OR that the CHO carbon atom is transformed into stipulate above 1 ＇-Y.R 2The reagent react of base prepares:
R 6-A 2R in-CHO (X IV) formula bAnd A 2Definition is with chemical formula IV, if desired, after this, with base-CH=C (OR 1 ＇) reduce so that chemical formula-CH to be provided 2-CHOR 1 ＇-base, if desired, after this remove any protecting group.
Best R bIt is the OH base of protection.
Can make compound (X IV) CHO carbon atom be transformed into the chemical formula-CH=CH (OR that stipulates above 1 ＇)-Y.R 2 ＇The suitable reagent of base be top definite chemical formula (X III) with as in required chemical formula II compound by R 1 ＇And R 2 ＇The compound of any protection form that character is determined.
The conditions suitable that reacts between chemical formula (X IV) compound and the mentioned reagent is similar to the described condition of reaction between top chemical formula (XII) and (X III) compound.
Chemical formula (XII) compound, particularly wherein m is 1, also can be prepared by the described method of EP0306228.
Chemical formula (XII B) compound is the known compound of buying, or by being used to prepare the compound of these compound similar approach preparations, or the compound that can be prepared by these compounds, for example is transformed into alkyl ester by the carbonyl acid that can buy.
Chemical formula (X III) compound is a compound known, or by the compound that is similar to the method preparation that is used to prepare known compound, and is for example at Annalen Chemie 1966,699,53 or J.Org.Chem.1983, disclosed in 48,3408.
Chemical formula (X IV) compound is a compound known, or by the compound that is similar to the method preparation that is used for preparing known compound, for example disclosed among the EP0306228.
(A represents chemical formula-CH to chemistry formula I compound in the formula 2-CH (OR 1)-part, wherein R 1The expression alkyl) or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing also can prepare by making chemical formula (X V) compound hydrolysis:
A 1-X-(CH 2) n-O-A 2-CH 2-CH (OR 1A in)-CN (X ＇) formula 1, A 2, R 1, x and n definition is with the chemical formula I, provides chemical formula I compound, wherein R 2Expression OH; If desired, after this will be the R of OH 2Be transformed into other R 2If desired, after this carry out one or n following arbitrary step:
(ⅰ) compound with chemical formula I is transformed into other chemical formula I compound;
(ⅱ) remove any protecting group; With
(ⅲ) pharmaceutical salts and/or its medicinal solvent thing of the chemical formula I compound of preparation.
Carry out the hydrolysis of chemical formula (X V) compound for the nitrile hydrolysis and can use general condition and reagent, for example use the basic hydrolysis of 10% sodium hydrate methanol solution.
Make R for OH 2Be transformed into other R 2Can finish for example following described method by using any proper method.
Chemical formula (X V) compound can be prepared by reacting with the trimethyl silicane prussiate by chemical formula (X VI) compound;
A 1-X-(CH 2) n-O-A 2-CH 2-CH (OR 1a)-OR 1bA in (X VI) formula 1, A 2, X and n definition is with chemical formula I, R 1a=R 1b, it represents alkyl.
Reaction between chemical formula (X VI) and the trimethyl silicane prussiate can be at inert solvent, for example in the methylene dichloride, is at room temperature below the room temperature and is preferably in the Lewis acid catalyst at low temperature, carries out under existing as boron-trifluoride etherate.
Chemical formula (X VI) compound can be prepared by reacting with chemical formula (X VIII) by chemical formula (X VII) compound:
A 1-X-(CH 2) n-O-A 2-CH=CH-OR 1aA in (X VII) formula 1, A 2, R 1a, X and n definition is as chemical formula (X V).
R 1aR in-OH (X VIII) formula 1aDefinition as above.
The reaction of suitably carrying out between chemical formula (X VII) and (X VIII) compound uses chemical formula (X VIII) compound as solvent, generally at high temperature, as under the solvent refluxing temperature, is preferably in tosic acid and exists down.
Best R 1aIt is methyl.
Chemical formula (X VII) compound can be transformed into the chemical formula-CH=CH-OR of afore mentioned rules by chemical formula (XII) compound (wherein m is 1) that makes afore mentioned rules and the CHO carbon atom that can make chemical formula (XII) 1The reagent react of base prepares, and suitable mentioned reagent is the Wittig reagent of chemical formula (X IX).
[Ph 3PCH 2-OR 1] +Cl -R in (X IX) formula 1Definition is with chemical formula I.
The reaction of carrying out between chemical formula (XII) and (X IX) compound can be under general Wittig reaction conditions, for example in aprotonic solvent (as tetrahydrofuran (THF)), at low temperature under room temperature, as in-10 ° of-25 ℃ of scopes, be at room temperature easily, and be preferably under inert atmosphere and the anhydrous condition.Best, before adding chemical formula (XII) compound, add alkali.As the suitable activating chemical formula of sodium hydride, n-Butyl Lithium or di-isopropyl lithamide (X IX) compound.
Chemical formula (X VIII) and (X IX) compound are compound known or by being similar to the compound for preparing the method preparation that known compound uses, for example at J.March, Advanced Organic Chemistry, 3rd Edition (1985), disclosed method among the Wiley Interscience.
Compound (the A wherein of chemistry formula I 3Be (CH 2) m-CH (OR 1)-, R 2Be that C-connects aromatic heterocyclic radical) or its isomeric form, and/or the activated form of compound that its pharmaceutical salts and/or its hydrate for medicinal use can be by the chemical formulas (XII) stipulated above and chemical formula (XX) compound is reacted and is prepared:
Figure C9310987400251
Het-CH is by R in the formula 2The aromatic heterocyclic radical of expression, it contains 1 carbon atom at least, after this with this compound (R in the formula 1Be hydrogen) be transformed into other R 1If desired, after this,
(ⅰ) compound with chemical formula I is transformed into other chemical formula I compound;
(ⅱ) remove any essential protecting group;
(ⅲ) pharmaceutical salts and/or its medicinal solvent thing of the chemical formula I compound of preparation.
The suitable activated form of chemical formula (XX) compound is the form of salt, as lithium salt form.
The activated form of chemical formula (XX) compound can (L be a leavings group in the formula by aromatic heterocyclic radical Het-CH or Het-CL, as halogen) and suitable common activator, for example salt agent (as lithium alkylide) in aprotonic solvent (as tetrahydrofuran (THF)) in accordance with known methods and technology (Adv.Heterocyclic chem for example, 1993,56,155, in disclosed) reaction prepare.
Chemistry formula I compound (A in the formula 3Be (CH 2) m-CH (OR 1)-, R 2Be that C-connects tetrazyl) or its isomeric form, and/or its pharmaceutical salts, and/or its hydrate for medicinal use, wherein heterocyclic radical can be by chemical formula (X XI) compound and azides ion source (as azide salt), and suitable is that an alkali metal azide (as trinitride sodium) reaction prepares.
Figure C9310987400261
A in the formula 1, A 2, R 1, X, m and n definition is with chemical formula I.
Chemical formula (X XI) compound can be used as POCl 3With chemical formula I compound (A in the formula 3Be (CH 2) m-CH (OR 1), ＇ YR 2Be CONH 2) dewatering prepares.
Reaction between chemical formula (X XI) compound and the azides ion source can under general condition be carried out, for example when sodiumazide is the azides ion source, reaction can be in aprotonic solvent (as dimethyl formamide), generally at high temperature (as the solvent refluxing temperature) is preferably under the trimethylsilyl chloride existence and finishes.
Above-mentioned chemical formula I compound is transformed into other chemical formula I compound and comprises:
A) a R base is transformed into another R base;
B) with an OR 1Base is transformed into another OR 1Base;
C) with a Y.R 2Base (wherein Y is CO) is transformed into another Y.R 2Base;
D) with a CO.R 2Base is transformed into additional C S.R 2Base; With
E) general-CH=C (OR 1)-Ji reduction or-CH 2-CH (OR 1) base.
Above-mentioned transformation can suitably be carried out on following any intermediate compound.
The transformation that chemical formula I compound is transformed into other chemical formula I compound can be used any suitable usual way.
It is that the base of hydrogen is transformed into the transformation that R is an acyl group that the suitable transformation that a R base is transformed into another R base comprises R; Carry out this transformation and can use suitable acylation process method commonly used, for example handle the chemical formula I compound of due care with acylating agent.Can prepare chemical formula I (R is an acetyl in the formula) compound with diacetyl oxide like this.
With an OR 1Base is transformed into another OR 1The suitable transformation of base comprises a kind of substituting group is transformed into another kind of substituent transformation, works as R 1When representing the alkyl of replacement, for example with CO 2R aSubstituting group (R in the formula aBe C 1-6Alkyl) reduction obtains CH 2The OH substituting group.
Carry out above-mentioned reduction and can use any common method of reducing, for example use the hydroborons reductive agent (as boron chloride sodium) in solvent (as methyl alcohol).
With a Y.OR 2Base (Y is CO in the formula) is transformed into another Y.R 2Suitable transformation comprise:
(ⅰ) with basic Y.R 3a(R in the formula 3aBe alkyl, aryl or aralkyl) be hydrolyzed into basic Y.OH, Y is CO in the formula.
(ⅱ) with basic R 2b(R in the formula 2bBeing alkoxyl group) amination becomes basic Y.NR 4R 5, Y is CO in the formula;
(ⅲ) the basic Y.OH halogenation of stipulating is above obtained corresponding acid halide, then the halogenide amination is obtained above-mentioned basic Y.R 4R 5, Y is CO in the formula;
(ⅳ) basic YOH esterification is obtained basic Y-O alkyl or Y-O aralkyl, Y is CO in the formula; With
(ⅴ) with basic Y.NH 2(Y is CO in the formula) is transformed into basic Y-C-Het, and Y is one and is good for that C-Het is the aromatic heterocyclic radical that C-connects.
The suitable method for hydrolysis that is used for C (ⅰ) transformation is general ester method for hydrolysis, for example uses the alkaline hydrated oxide methanol aqueous solution.
C (ⅱ) or c (ⅲ) change suitable amination method and comprise method in common, for example are used in the ammonia treatment in tetrahydrofuran (THF)/methyl alcohol.
Change suitable halogenation method for c (ⅲ) and comprise method in common, for example handle with oxalyl chloride.
Changing suitable souring method for c (ⅳ) is method in common, use suitable alkanol [as methyl alcohol] in the presence of a kind of acid, can prepare alkyl ester like this, can prepare aralkyl ester by handling salt YOH base (as sodium salt) with suitable aralkyl halogen (as bromotoluene).
With basic Y.NH 2The suitable transformation that (Y is CO in the formula) is transformed into basic Y-C-Het (Y is a key in the formula, and C-Het is that C-connects aromatic heterocyclic radical) comprises:
A) obtain 1,2 ＇, 4-triazole with hydrazine (as hydrazine hydrate) and acid amides acetal (as dimethylformamide dimethyl acetal) reaction; Or
B) obtain 1,2, the 4-oxadiazole with oxyamine (as the oxyamine hydrochloride) and acid amides acetal (as dimethylformamide dimethyl acetal) reaction.
With basic CO.R 2Be transformed into other basic CS.R 2The available method in common of suitable transformation finish, for example use Lawesson ' the s reagent in solvent (as toluene), under any temperature that the speed accepted that forms desired product is provided.Generally under the solvent refluxing temperature.
With base-CH=C (OR 1)-suitably is reduced into base-CH 2CH (OR 1Any reduction process easily of)-can use, catalytic reduction or metal/solvent reduction method for example, as previously mentioned.
Can estimate that any reactive group in the Substrate molecule can be according to common chemistry practice protection in the above-mentioned arbitrary reaction that comprises (a) and (b), (c), (d) and (e) transform.
Appropriate protection base in above-mentioned any reaction is commonly used in the prior art.The suitable hydroxyl protecting group that for example comprises benzyl or trialkylsilkl.
The method that forms and remove these protecting groups is those usual ways that are fit to the protection molecule.For example preparing benzyloxy can be by handling suitable compound with benzyl halide (as bromotoluene), and if desired, benzyl is removed in after this available catalytic hydrogenation or slight ether-splitting agent (as trimethyl silicane iodine or boron tribromide) easily.
Chemistry formula I compound contains suitable isomery shape and its pharmaceutical salts and can be used as single isomer and prepare with common chemical technology method.
But,, provide new processing method for separating these compound optically active isomers for the compound of some chemical formula I.Certainly, new disclosed processing method is to separate the optically active isomer of any compound, as long as the chiral carbon of this compound is received carboxyl ester and basic OZ 1(Z in the formula 1Be alkyl, aryl or aralkyl) on.
So the present invention is that the optically active isomer of separating compound (Substrate ester) provides a kind of processing method, above-claimed cpd contains chemical formula (H) part:
Figure C9310987400291
C* is a chiral carbon in the formula, and Z is C 1-12Alkyl, Z 1Be C 1-12Alkyl, aryl or aryl C 1-12Alkyl, this processing method comprise with lipase (from Rhizopus delemar, Rhizopus arrhizus, Rhizopus LIPF4 or from Mucormiehei) with the ester group CO of an enantiomorph 2The Z mapping selectively is hydrolyzed into carboxyl, after this, as needs, segregation spissated product carboxylic acid of mapping or spissated Substrate ester.
Spissated product carboxylic acid of mapping and/or the spissated Substrate ester of mapping can be with general extraction process segregations, as are separated and/or are extracted in the suitable solvent, if desired, but stratographic analysis after this.
In replacing segregation process, before the segregation, the spissated Substrate ester of mapping can transfer into corresponding carboxylic acid to by hydrolysis, and available then common method is emanated it.Under a suitable situation of the present invention, handle the spissated Substrate ester of hydrolyzable mapping with above-mentioned lipase.To obtain corresponding carboxylic acid.
The compound that drops on the chemical formula I in the chemical formula (H) is those compounds, wherein 2 expression R 3, Z 1Expression R 1: use new process can prepare the spissated chemical formula I compound of mapping, wherein A like this 5Expression (CH 2) m-CH (OR 1)-, Y represents CO, R 2Be OR 3, and A 1, A 2, R 1, X, m and n definition is with chemical formula I (after this using chemical formula (I A) to substitute).
Microbial lipase can obtain by general culture technique, J.Bacteriol for example, and 1982, vol, 150498-505.H.Gilbert and M.Tully, disclosed among european patent application NO.0198440 and the English Patent No.1474519.This lipase can be emanated and is pure enzyme, or changes a kind of method, can make the source of suitable lipase enter reaction.
Best, obtain microbial lipase to buy the enzyme preparation of purifying or partly purifying.
The hydrolysis of carrying out chemical formula (H) compound can have in the suitable water solvent of controlling PH any, for example in aqueous buffer or in by the solvent that adds aqueous sodium hydroxide solution control pH value, pH value provides the appropriate speed that forms desired product, PH is generally in the 5-9 scope, for example in the 6-8 scope, as at PH7.
Hydrolysis can be carried out providing under any temperature that forms the suitable speed of desired product, generally at low temperature to room temperature, for example in 5-40 ℃ of scope, for example in 20-40 ℃ of scope, be preferably in 20-30 ℃, as 23 ℃.
Generally, the Substrate mixture is introduced reactive system with the solution form in organic solvent, and it can be that water can miscible liquor, acetone for example, tetrahydrofuran (THF), methyl-sulphoxide, dimethyl formamide or acetonitrile.
The solid of selecting hydrolysis to have identical stereochemical compound (I A) is selected technology at (-) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] oxyethyl group] phenyl]-2-methoxy propionic acid in, beating on the asterisk carbon atom as equivalent carbon.
Reaction conditions, for example specific acid pH value and temperature of reaction, it provides best concentrating for specific mapping enriched compound (H), and this condition can be determined by the experiment of routine.
Suitably, stereoselective reaction provides greater than the spissated compound of the mapping of the required enantiomorph of 70%W/W (I A), and is suitable for 80%W/W.Optimum, the three-dimensional handicraft product of selecting provides mapping enriched compound (I A), wherein required enantiomorph 80-100%W/W, and 90-100% preferably, as 90-95%, best 95-100% is as 95%, 96%, 97%, 98%, 99% or 100%W/W.
Study the spissated compound of above-mentioned mapping (I A) to form other target of the present invention.So, the invention provides mapping enriched compound (I A) or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing.
The present invention also provides the spissated compound of mapping (I A) or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing, and wherein required isomer is greater than 50%W/W.Suitable more suitable optimum greater than 80%W/W greater than 70%W/W, the isomer 80-100%W/W of chemical formula (I A) compound that mapping enriched compound (I A) is wherein required, better 90-100%, as 90-95%, best 95-100% is as 95%, 96%, 97%, 98%, 99% or 100%W/W.
At compound or its isomeric form and/or its pharmaceutical salts and/or its a medicinal solvent thing that chemical formula (I A) is provided under the situation preferably, preferably with optically pure form.
The absolute stereo chemistry of compound can use usual method, determines as the X-radiocrystallgraphy.
As mentioned above, The compounds of this invention has useful therapeutic: thus the invention provides chemical formula I compound or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing, for being used as the active treatment thing.
Like this, the invention provides chemical formula I compound, or its isomeric form and/or its pharmaceutical salts and/or medicinal solvent thing, for being used for the treatment of and/or preventing hyperglycemia.
Another purpose, the present invention also provides chemical formula I compound, or its isomeric form and/or its pharmaceutical salts and/or medicinal solvent thing, for being used for the treatment of and/or preventing hyperlipidemia.
As previously mentioned, the present invention also provides chemical formula I compound or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing, is used for the treatment of hypertension, cardiovascular disorder and some drinking and eating irregularly.
Cardiovascular disorder is particularly including atherosclerosis.
The imbalance of some secondary eclipses particularly including appetite stimulator imbalance relevant with few food (as anorexia nervosa) with feed and with the relevant imbalance of super food the (as obesity and anorexia Bulimia nerovsa).
Chemistry formula I compound, but or its isomeric form and/or its pharmaceutical salts and/or medicinal solvent thing self administration or best also to comprise drug composition administration with carrier.
So the present invention also provides and contains logical formula I compound, or its isomeric form, or its pharmaceutical salts, or the pharmaceutical composition of its medicinal solvent thing and its pharmaceutical carrier.
Term " pharmaceutical " used herein comprises people and compound for animals, composition and Synergist S-421 95: for example term " pharmaceutical salts " comprises salt for animals.
If desired, composition can be with writing or print the packaged form of operation instruction.
General pharmaceutical composition of the present invention is fit to oral, though composition is estimated also can pass through the additive method administration, for example absorbs by injection with through skin.
Being particularly suitable for oral composition is unit dosage form, as tablet and capsule.Other are unit dosage form fixedly, as the powder in the capsule of packing into also can use.
Can comprise thinner, filler, disintegrating agent, wetting agent, lubricant, staining agent, spices or other common auxiliarys according to common medicinal practice carrier.
General carrier comprises, for example Microcrystalline Cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, Magnesium Stearate or Sodium Lauryl Sulphate BP/USP.
Onlyly be, with composition with the unit dosage form prescription.Unitary dose generally contains activeconstituents 0.1-1000mg, 0.1-500mg more generally, more special 0.1-250mg.
The present invention further provides the method that treats and/or prevents people or non-human mammal hyperglycemia, it comprises the compound of the atoxic logical formula I of supplying with hyperglycemia people or non-human mammal (when needing) significant quantity, or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing.
The present invention further provides the method for treatment people or non-human mammal hyperlipidemia, this method comprises the chemical formula I compound of the non-poison of the people that supplies with hyperlipidemia when needed or non-human mammal significant quantity, or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing.
Suitably, activeconstituents can the aforementioned pharmaceutical compositions administration, and this is a specific purpose of the present invention.
Treating and/or preventing hyperglycemia patient, and/or treat and/or prevent the high fat of blood man-hour, can the formula I compound will be led to, or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing according to dosage supply medicine, for example above-mentioned described, one day one to six time, every day, total dose was generally 0.1-6000mg for the adult of 70Kg, 1-1500mg more commonly used.
Treating and/or preventing the hyperglycemia non-human mammal, during specific dog, can oral effective constituent, usually once a day or secondary, consumption is about 0.025mg/Kg to 25mg/kg, for example 0.1-20mg/kg.Similar dosage is suitable when treating and/or preventing the hyperlipidemia non-human mammal.
Treatment hypertension, the dosage of cardiovascular disorder and drinking and eating irregularly are generally with the dosage of above-mentioned treatment hyperglycemia.
Another purpose the invention provides chemical formula I compound or its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing purposes, is used for making the medicine that treats and/or prevents hyperglycemia.
The present invention also provides chemical formula I compound, or the purposes of its isomeric form and/or its pharmaceutical salts and/or its medicinal solvent thing, is used for making treating and/or preventing hyperlipidemia, the medicine of hypertension, cardiovascular disorder or some drinking and eating irregularly.
Chemistry formula I compound has been proved toxic effects at above-mentioned dosage range.
Following processing method and embodiment illustrate the present invention but do not limit the present invention in any way.
Embodiment 1 ethyl 3-[4-[2-[N-2-benzoxazolyl)-and the N-methylamino-] oxyethyl group] phenyl]-2-methoxy propyl acid esters
Figure C9310987400341
(60% is dispersed in the oil with sodium hydride under nitrogen atmosphere; 0.47g) portion-wise addition was to what stirred, ice ethyl 3-(4-hydroxyphenyl)-2-methoxy propyl acid esters (2.38g) but is at anhydrous N, in the solution in the dinethylformamide (50ml).In room temperature mixture being stirred 30 minutes, adds 2-[N-(2-benzoxazolyl)-N methylamino-then] ethanol sulfonyloxy methyl ester (the open No.0306228 of european patent application) is (2.86g) at N, the solution in the dinethylformamide (90ml).At 80 ℃, cooling also concentrated under vacuum with mixture heating up 17 hours.(3 * 200ml) extract with resistates water (200ml) dilution and with ethyl acetate.With the organic solution water that merges (3 * 100ml) washings, with salt solution (200ml) washing, dry (MgSO 4) and evaporation, to obtain a kind of glue.On silica gel,, make eluent, obtain gluey title compound with methylene dichloride with 10% ethyl acetate chromatographic separation
1H?NMRδ(CDCl 3)
1.22 (3H, t); (2.95 2H, complex spike); 3.33 (3H, S); 3.34 (3H, s); 3.89 (1H, dd); 3.93 (2H, t); 4.17 (2H, q); 4.24 (2H, t); 6.81 (2H, d); And 6.90-7.40 (6H, complex spike).
Embodiment 2:3[4-[2-N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxypropionic acid
In room temperature with ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-phenyl]-2-methoxy propyl acid esters (1.5g).The mixture of 10% aqueous sodium hydroxide solution (7.5ml) and methyl alcohol (23mt) stirred 1.5 hours, and dilute with water (600ml) arrives PH2 with methylene dichloride (300ml) washing and with hcl acidifying then.With mixture with ethyl acetate (3 * 300ml) extractions, with the ethyl acetate solution water that merges (2 * 200ml) and salt solution (200ml) washing, drying (MgSO 4) and evaporation.Crystallization goes out resistates from ethyl acetate-methylene dichloride-hexane, obtains title compound, mp150-153 ℃.
1H?NMRδ(CDCl 3)
2.80 (1H, dd); 2.91 (1H.dd); 3.25 (3H, s); 3.27 (3H, s); 3.83 (1H, dd); 3.90 (2H, t); 4.22 (2H, t); (6.75-7.40 8H, complex spike); With 12.60 (1H, broad peak are used D 2The O exchange).Embodiment 3 methyl 3-[4-[2-N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-methoxy propyl acid esters
Prepare title compound, glue with embodiment 1 similar method by methyl 3-(4-hydroxyphenyl)-2-methoxy propyl acid esters.
1H NMR δ (CDCl 3) 2.95 (2H, complex spikes); 3.33 (3H, s); 3.34 (3H, s); 3.70 (3H, S); (3.90 3H, complex spike); 4.24 (2H, t); 6.80 (2H, d); And 7.00-7.40 (6H, complex spike).
Embodiment 4 methyl 2-methoxyl group-3-[4-[2-(N-methyl-N-[2-pyridyl) amino] oxyethyl group]-phenyl] propionic ester
Figure C9310987400371
With 2-methoxyl group-3-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group]-phenyl] propionitrile (1.15g), sodium hydroxide solution (10%W/V, 10ml) and the heating 2.5 hours under refluxing of the mixture of methyl alcohol (20ml), cooling and with rare HCl PH7 that neutralizes.The vaporising under vacuum mixture dissolves in resistates with in hydrogen chloride gas presaturation and the methyl alcohol again.Mixture was at room temperature placed 7 days, then evaporation.Add saturated sodium bicarbonate solution (100ml), and (3 * 200ml) extract suspension with ethyl acetate.With the ethyl acetate solution water that merges (2 * 500ml) and salt solution (500ml) washing, drying (MgSO 4) and evaporation.With the glue that obtains on silica gel with 1% methyl alcohol chromatographic separation, use the methylene dichloride wash-out, obtain gluey title compound.
1H?NMRδ(CDCl 3)
(2.94 2H, complex spike); 3.14 (3H, s); 3.33 (3H, s); 3.71 (3H, s); 3.94 (1H, dd); 3.96 (2H, t); 4.15 (2H, t); (6.55 2H, complex spike); 6.81 (2H, d); 7.11 (2H, d); (7.45 1H, complex spike); With 8.15 (1H, dd).Embodiment 53-[4-[2-N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxyl group] propionic acid amide
Figure C9310987400381
In room temperature with methyl 3-[4-[2-N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxyl group] propionic ester (1.00g), tetrahydrofuran (THF) (20ml), (proportion 0.88,20ml) mixture stirred 4 hours for methyl alcohol (20ml) and ammoniacal liquor.Add another part ammoniacal liquor (20ml), continued to stir 50 hours altogether in room temperature.Under vacuum mixture is concentrated, dilute with water (500ml) resistates is with (3 * 200ml) extractions of ethyl ester ethyl ester.With the ethyl acetate solution water (500ml) that merges, salt solution (500ml) washing, dry (MgSO 4) and evaporation.Crystallization goes out resistates from methylene dichloride-hexane, obtains title compound, mp133-5 ℃.
1H?NMRδ(CDCl 3)
2.88 (1H, dd); 3.07 (1H, dd); 3.33 (3H, s); 3.34 (3H, s); 3.80 (1H, dd); 3.94 (2H, t); 4.24 (2H, t); 5.41 (1H, 6r); Use D 2The O exchange); 6.33 (1H, br use D 2The O exchange); 6.80 (2H, d); 7.00 (1H, t); 7.13 (2H, d); 7.14 (1H, app.t); 7.25 (1H, d); With 7.33 (1H, d).
Embodiment 6 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy propylene acid esters
Under nitrogen atmosphere with triethyl 2-oxyethyl group phosphine acyl acetic acid ester (W.Grell δ H.Machleidt, Annalen.chemie, 1966,699,53) (1.98g) solution in anhydrous tetrahydro furan (25ml) slowly is added to and stirred, and ices cool sodium hydride (suspension in 60% oil but; 0.33g) in the suspension in anhydrous four furans (5ml).At 0 ℃ mixture was stirred 30 minutes, adds 4-[2-[N-(2-benzoxazolyl)-N-methylamino-then] oxyethyl group] solution of phenyl aldehyde (2.169g) in anhydrous tetrahydro furan (15ml).Mixture heat to room temperature, was stirred other 20 hours.Evaporating solvent is suspended in resistates in the water (300ml), with ethyl acetate (3 * 250ml) extractions.With the ethyl acetate layer water that merges (2 * 1l), salt solution (1L) washing, dry [MgSO 4] and evaporation.With resistates on silica gel with 2.5% ethyl acetate chromatographic separation, make eluent with methylene dichloride, obtain gluey title compound, be 62: 38 Z of two strong isomer: the E mixture is (by the alkene mark 1H NMR integration)
1H?NMRδ(CDCl 3)
1.10-1.50 (6H, complex spike, isomer OCH 2CH 3The mixture of mark); 3.35 (3H, s, NMe); 3.85-4.30 (8H, complex spike, isomer OCH 2CH 3And NCH 2CH 2The mixture of O mark); 6.02 (0.38H *S, E-olefinic proton); (6.75-7.70 8H, complex spike, isomer aromatics proton); With 6.91 (0.62H *, s, 2-olefinic proton).
Two mark H* constitute olefinic proton mark together.(ratio of Z: E is 62: 38) the record chemical shift simulation (cfR.A.Aitken and G.L.Thom, Synthesis, 1989,958) of arranging of main Z isomer with similar olefinic proton.Embodiment 7 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-phenyl]-2-phenoxy group acrylate
With being similar to embodiment 6 described methods; when making triethyl 2-phenoxy group phosphine acyl acetic acid ester (0.94g) and 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] when phenyl aldehyde (0.89g) reacts; obtain gluey title compound, 1: 1 double bond isomer mixture (by 1The ratio that H NMR determines).
1H?NMRδ(CDCl 3)
1.05 and 1.08 (mixing 3H, isomer OCH 2CH 3The triplet mark); 3.31 and 3.35 (mixing 3H, isomer NM 2Mark); 3.85-4.30 (6H, complex spike, isomer OCH 2CH 3And NCH 2CH 2The O mark); And 6.70-7.70 (14H, complex spike, aromatics and olefinic mark).
Embodiment 8 ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-phenyl]-the 2-phenoxypropionic acid ester
With ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-phenyl]-2-phenoxypropionic acid ester (0.97g) dissolves in the diox (100ml), at room temperature with 22psi pressure under in 10% palladium charcoal (200mg) hydrogenation totally 7 hours down.By flocculating aids solution is filtered and evaporation.On silica gel with 5% ethyl acetate with the resistates chromatographic separation, make elutriant with methylene dichloride, obtain gluey title compound.
1H?NMRδ(CDCl 3)
1.18 (3H, t); (3.17 2H, app d); 3.33 (3H, t); 3.93 (2H, t); 4.13 (2H, g); 4.25 (2H, t); 4.71 (1H, dd); 6.81 (2H, d); And 6.90-7.40 (11H, complex spike).
Embodiment 9
3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-phenoxy propionic acid
Figure C9310987400412
According to being similar to embodiment 2 described methods by ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-phenoxypropionic acid ester (0.88g) acquisition title compound, mp162-4 ℃.(methyl alcohol).
1H?NMRδ(DMSO-d 6)
(3.10 2H, complex spike); 3.21 (3H, s); 3.87 (2H, t); 4.21 (2H, t); 4.83 (1H, dd); (6.75-7.40 13H, complex spike); With 13.00 (1H, br use D 2The O exchange).
Embodiment 10
Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy-c acid esters
Figure C9310987400421
Add rhodium acetate (II) dipolymer (33mg) to methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-mixture of 2-diazo propionic ester (2.80g), ethanol (2.16ml) and benzene (50ml) in.At room temperature under nitrogen atmosphere mixture was stirred 15 minutes, heating down another 15 minutes, cooling and vaporising under vacuum then reflux.With resistates on silica gel with 1.5% methyl alcohol chromatographic separation, make elutriant with methylene dichloride, obtain gluey title compound.
1H?NMR?δ(CDCl 3)
1.14 (3H, t); 2.93 (2H, app, d); (3.31 1H, complex spike); 3.32 (3H, s); (3.57 1H, complex spike); 3.69 (3H, s); (3.93 3H, complex spike); 4.23 (2H, t); 6.79 (2H, d); 7.00 (1H, t); (7.14 3H, compound honeybee); 7.25 (1H, d); With 7.36 (1H, d).
Embodiment 11 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-isopropoxy propionic ester
Figure C9310987400431
According to being similar to embodiment 1 described method by methyl 3-(4-hydroxyphenyl)-2-isopropoxy propionic ester (1.34g) preparation title compound, glue.
1H?NMRδ(CDCl 3)
0.94 (3H, d); 1.13. (3H, d); (2.87 2H, complex spike); 3.34 (3H, s); (3.47 1H, complex spike); 3.70 (3H, s); 3.93 (2H, t); 4.00 (1H, dd); 4.23 (2H, t); 6.79 (2H, d); 7.00 (1H, t); (7.17 3H, complex spike); 7.25 (1H, d); With 7.36 (1H.d).Embodiment 12 methyl 3-[4-[2-[N-(2-benzoxazolyl group)-N-methylamino-] oxyethyl group] phenyl]-2-propoxy-propionic ester
According to being similar to embodiment 1 described method by methyl 3-(4-hydroxyphenyl)-2-propoxy-propionic ester (0.88g) preparation buttery title compound.
1H NMR δ (CDCl 3) 0.83 (3H, t); (1.52 2H, composite members); (2.93 2H, recombiner); (3.71 1H, complex spike); 3.34 (3H, s); (3.50 1H, complex spike); 3.69 (3H, s); (3.85-4.00 3H, composite members); 4.22 (2H, t); And 6.75-7.40 (8H, complex spike).
Embodiment 13
3-[4-[2-[N-(2-benzoxazolyl group)-N-methylamino-] oxyethyl group] phenyl]-2-propoxy-propionic acid is according to being similar to embodiment 2 described methods by methyl 3-[4-[2-[N-(2-benzoxazolyl group)-N-methylamino-] oxyethyl group] phenyl]-2-propoxy-propionic ester (1.50g) prepares gluey title compound.Should use in the salt formation step, not be further purified.
1H NMR δ (CDCl 3) 0.85 (3H, t); 1.53 (2H, t); (3.00 2H, complex spike); (3.29 1H, complex spike); 3.32 (2H, t); (3.52 1H, complex spike); 3.91 (2H, t); 4.02 (1H, dd); 4.18 (2H, t); 5.80 (1H, br use D 2The O exchange); 6.77 (2H, d); And 6.95-7.40 (6H, complex spike).Embodiment 143-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-propoxy-propionic acid, sodium salt
Figure C9310987400451
Sodium methylate (0.11g) is added to 3-[4-[2-[N-(2-the benzoxazolyl)-N-methylamino-that stirred] oxyethyl group] phenyl]-solution of 2-propoxy-propionic acid (0.81g) in methyl alcohol (10ml) in.Stir after 5 minutes, with the mixture evaporation, then by ether (10ml is each) revaporization secondary.To obtain glue with the development of ebullient ethyl acetate, filter, and filtrate is concentrated and dilute with ether.With the solid filtering that obtains and dry under vacuum, obtain title compound, mp210-4 ℃.
1H?NMRδ(DMSO-d 6)
0.67 (3H, t); (1.35 2H, complex spike); 2.65 (1H, dd); 2.85 (1H, dd); (3.02 1H, complex spike); 3.25 (3H, s); (3.35 1H, complex spike); 3.70 (1H, dd); 3.90 (2H, t); 4.27 (2H, t); 6.80 (2H, d); And 7.00-7.40 (6H, complex spike).
Embodiment 15
Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methoxyl group phenoxy group) acrylate
According to being similar to embodiment 6 described modes; when making triethyl 2-(4-methoxyl group phenoxy group) phosphine acyl acetic acid ester (2.00g) and 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-when phenyl aldehyde (1.71g) reacts; obtain gluey title compound, the mixture of a kind of 1: 1 double bond isomer (by 1The ratio that H NMR determines). 1H NMR δ (CDCl 3) 1.08 and 1.19 (mixing 3H, isomer OCH 2CH 3The triplet mark), 3.32 and 3.34 (mix 3H, NMe is unimodal); 3.75 and 3.77 (mix 3H, OMe is unimodal); (3.95 2H, complex spike); (4.05-4.35 4H, complex spike); (6.55 0.5H, s, E-isomer olefinic proton); And 6.75-7.70 (12.5H, complex spike).Embodiment 16 ethyl 3-(4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methoxyl group phenoxy group) propionic ester
Figure C9310987400471
According to being similar to embodiment 8 described processing methodes, make solvent by ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-with ethanol] oxyethyl group] phenyl]-2-(4-methoxyl group phenoxy group) propionic ester prepares gluey title compound.
1H?NMRδ(CDCl 3)
1.18 (3H, t); 3.15 (2H, app, d); 3.33 (3H, s); 3.72 (3H, s); 3.93 (2H, t); (4.15 4H, complex spike); 4.62 (1H, t); 6.75 (4H, s); 6.81 (2H, d); And 6.95-7.40 (6H, complex spike).Embodiment 173-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methoxyl group phenoxy group) propionic acid. According to being similar to embodiment 2 described methods by ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methoxyl group phenoxy group) propionic ester (1.62g) acquisition title compound, mp148-50 ℃ (methyl alcohol).
1H?NMRδ(CDCl 3)
3.20 (2H, d); 3.27 (3H, s); 3.71 (3H, s); 3.85 (2H, t); 4.07 (2H.t); 4.72 (1H, t); (6.70-7.30 12H, complex spike); With 9.05 (1H, br use D 2The O exchange).Embodiment 18 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methylphenoxy) acrylate.
According to being similar to embodiment 6 described methods, prepare title compound by triethyl 2-(4-methylphenoxy) phosphine acyl acetic acid ester, the mixture of a kind of 1: 1 double bond isomer, obtained is a kind of colloid.
1H?NMRδ(CDCl 3)
1.07 and 1.19 (mixing 3H, isomer OCH 2CH 3The triplet mark); 2.27 and 2.29 (mix 3H, Me is unimodal); 3.31 and 3.34 (mixing 3H, the NMe mark); (3.90 2H, complex spike); (4.05-4.35 4H, complex spike); 6.64 (0.5H, s, E-bisabolene isomer body; And 6.75-7.70 (12.5H, complex spike).Embodiment 19
Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-) oxyethyl group] phenyl]-2-(4-methylphenoxy) propionic ester.
Figure C9310987400491
According to being similar to embodiment 8 described methods, make solvent with ethanol, by ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methylphenoxy) acrylate prepares gluey title compound.
1H?NMRδ(CDCl 3)
1.18 (3H, s); 2.24 (3H, s); (3.15 2H, complex spike); 3.33 (3H, s); 3.93 (2H, t); 4.17 (2H, q); 4.23 (2H, t); 4.67 (1H, t); 6.71 (2H, d); 6.81 (2h, d); And 6.95-7.40 (8H, complex spike);
Embodiment 203-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methylphenoxy) propionic acid
Figure C9310987400492
According to being similar to embodiment 2 described methods, by ethyl 3-[4-[2-(N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-methylphenoxy) propionic ester obtains title compound, mp150-151 ℃ (methyl alcohol).
1H NMR (CDCl 3) 2.33 (3H, s); 3.21 (2H, d); 3.26 (3H, s); 3.84 (2H, t); 4.06 (2H, t); 4.77 (1H, t); (6.75 4H, complex spike); (6.95-7.30 8H, complex spike); With 7.35 (1H, br D 2The O exchange).Embodiment 21
Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methylphenoxy) acrylate
Obtain gluey title compound according to being similar to embodiment 6 described methods by triethyl 2-(2-methylphenoxy) phosphine acyl acetic acid ester, the ratio of double bond isomer 44: 56 (by 1H NMR measures). 1H NMR δ (CDCl 3) 1.06 and 1.114 (mixing 3H, isomer OCH 2CH 3The triplet mark); 3.32 and 2.42 (mix 3H, methyl is unimodal); (4.14 2H, compound honeybee); (4.26 2H, complex spike); (6.48 0.44H, E-olefinic proton); (7.28 0.56H, Z-olefinic proton); And 6.70-7.65 (12H, compound honeybee).Embodiment 22 ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methylphenoxy) propionic ester
Figure C9310987400511
According to being similar to embodiment 8 described methods, make solvent with ethanol, by ethyl (E/Z)-3-(4-[2-[N-(2 ＇ ,-benzoxazolyls)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methylphenoxy) acrylate prepares gluey title compound.
1H?NMR(CDCl 3)
1.18 (3H, t); 2.21 (3H, s); 3.18 (2H, d); 3.33 (3H, s); 3.93 (2H, t); 4.16 (2H, q); 4.23 (2H, t); 4.72 (1H, t); 6.57 (1h, d); And 6.70-7.40 (11H, complex spike).
Embodiment 23
3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methylphenoxy) propionic acid
Figure C9310987400512
According to be similar to embodiment 2 described methods by ethyl 3-(4-[2-(and N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methylphenoxy) propionic ester prepares title compound, mp142-3 ℃ (methylene dichloride-hexane). 1H NMR δ (CDCl 3) 2.25 (3H, s); 3.25 (2H, d); 3.27 (3H, s); 3.83 (2H, t); 4.04 (2H, t); 4.82 (1H, t); (6.65-7.40 12H, complex spike); With 7.88 (1H, br use D 2The O exchange).Embodiment 24 methyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-chlorophenoxy) acrylate
Figure C9310987400521
According to being similar to embodiment 6 described modes; when making methyl diethyl 2-(4-chlorophenoxy) phosphine acyl acetic acid ester and 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] when phenyl aldehyde reacts; obtain gluey title compound, the mixture of 1: 1 double bond isomer. 1H NMR δ (CDCl 3) 3.31 and 3.35 (mix 3H, NMe is unimodal); 3.65 and 3.74 (mix 3H, OMe is unimodal); (3.93 2H, complex spike); (4.25 2H, complex spike); And 6.70-7.70 (13H, complex spike).Embodiment 25 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-chlorophenoxy) propionic ester
Figure C9310987400531
Magnesium chips (0.5g) is added to methyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-in room temperature] oxyethyl group] phenyl)-2-(4-chlorophenoxy) acrylate (0.98g) and being dissolved in the mixture of iodine crystal of methyl alcohol (50ml).With heating rod mixture is slowly heated up to the reaction end, at this moment stop heating, (approximately above 5 minutes) stir mixture during room temperature is being added another part magnesium (2.00g).Immerse reaction mixture in the cooling bath and continue to be stirred to all dissolving metals (～4 hours), then evaporating mixture in a vacuum.Resistates is suspended in the water (100ml), during adding concentrated hydrochloric acid, firmly stirs, obtain (when all suspended substances dissolve) final pH value 1.5.(2 * 100ml) extraction mixtures are then with the ethyl acetate layer water (500ml), salt solution (300ml) washing that merge, dry (MgSO with ethyl acetate 4) and evaporation.With the glue that obtains on silica gel with 3% ethyl acetate chromatographic separation, make elutriant with methylene dichloride, obtain title compound, mp88-90 ℃. 1H NMR δ (CDCl 3) 3.15 (2H, d); 3.33 (3H, s); 3.69 (3H, s); 3.93 (2H, t); 4.23 (2H, t); 4.69 (1H, t); 6.73 (2H, d); 6.81 (2H, d); And 6.95-7.40 (8H, complex spike).Embodiment 263-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-chlorophenoxy) propionic acid
According to being similar to embodiment 2 described processing methodes by methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-chlorophenoxy) propionic ester prepares title compound, mp 164-5 ℃ (methyl alcohol) 1H NMR δ (CDCl 3) 3.22 (2H, complex spikes); 3.26 (3H, s); (3.84 2H does not resolve t); (4.02 2H does not resolve t); 4.79 (1H, t); 6.75 (2H, d); 6.83 (2H, d); And 6.95-7.30 (9H, compound honeybee); Use D 2When shaking, O reverts to 8H).Embodiment 27 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(4-chlorophenoxy) propionic ester
Under nitrogen atmosphere with sodium hydride (60% dispersion at mineral oil; 0.14) join methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2 hydroxy propanoic acid ester (1.20g) is at anhydrous N, in the solution of the stirring in the dinethylformamide (20ml). in batchesIn room temperature mixture was stirred 15 minutes, add bromotoluene (0.6ml) afterwards.Continue to stir 3 hours in room temperature, then 80 ℃ 17 hours, afterwards with the mixture cooling, water (500ml) dilution and with ethyl acetate (3 * 200ml) extract.With the ethyl acetate layer water that merges (4 * 500ml) and salt solution (500ml) washing, dry (MgSO4) and evaporate.With resistates on silica gel with 1% methyl alcohol chromatographic separation, use the methylene dichloride wash-out, obtain gluey title compound, it is not further purified and is used to next procedure. 1H NMR δ (CDCl 3) 2.98 (2H, complex spikes); 3.36 (3H, s); 3.70 (3H, s); 3.95 (2H, t); 4.07 (1H, dd); 4.25 (2H, t); 4.35 (1H, d); 4.64 (1H, d); 6.80 (2H, d); And 6.95-7.45 (11H, complex spike).Embodiment 283-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(phenyl methoxyl group) propionic acid
Figure C9310987400561
According to being similar to embodiment 2 described processing methodes, by methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(phenyl methoxyl group) propionic ester prepares foamed title compound.This material is not further purified and is directly used in the salt formation step. 1H NMR δ (CDCl 3) 3.00 (1H, dd); 3.10 (1H, dd); 3.32 (3H, s); 3.90 (2H, t); (4.16 3H, complex spike); 4.45 (1H, d); 4.67 (1H, d); 4.75 (1H, broad peak are used D 2The O exchange); 6.78 (2H, d); And 6.95-7.45 (1H, complex spike).Embodiment 293-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(phenyl methoxyl group) propionic acid, sodium salt
Figure C9310987400562
It is cool but to add sodium methylate (0.031g) to ice, the 3-[4-[2-[N-that stirred (2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-solution of 2-(phenyl methoxyl group) propionic acid (0.26g) in methyl alcohol (5ml) in.At 0 ℃ mixture was stirred 10 minutes, use ether (10ml) dilution and evaporation then.Resistates stirred and from ether (10ml is each) revaporization several times up to obtaining solid.Solid filtered by ether and under vacuum 60 ℃ of 1 weeks of drying, obtain title compound, a kind of free-pouring powder.
1H?NMRδ(DMSO-d 6)
2.67 (1H, dd); 2.90 (1H, dd); 3.23 (3H, s); 3.62 (1H, dd); 3.88 (2H, t); 4.15 ((1H, dd); 4.18 (2H, t); 4.63 (1H, d); 6.81 (2H, d); And 6.95-7.45 (1H, complex spike).Embodiment 30 ethyls (E/Z)-4-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(oxyethyl group but-2-ene acid esters)
According to being similar to embodiment 6 described methods by 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl acetaldehyde prepares gluey title compound, and with the mixture segregation of 1: 1 double bond isomer. 1H NMR δ (COCl 3) 1.25-1.50 (6H, complex spike); 3.34 (3H, s); 3.50 (0.5 * 2H.d); 3.72 (2H, t); (3.90 3H, complex spike); (4.20-4.35 4H, complex spike); 5.29 (0.5H, t); 6.36 (0.5H, t); 6.78 (2H, d); And 6.90-7.40 (6H, complex spike).
Embodiment 31 ethyl 4-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-oxyethyl group butyric ester
Figure C9310987400581
According to being similar to embodiment 8 described methods by ethyl (E/2)-4-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-(oxyethyl group but-2-ene acid esters prepares gluey title compound to 2-, makes solvent with ethanol. 1H NMR δ (CDCl 3) 1.26 (6H, complex spikes); 1.97 (2H, q); (2.68 2H, complex spike); 3.35 ((3H, s); 3,37 (1H, complex spikes); (3.63 1H, complex spike); 3.75 (1H, t); 3.94 (2H, t); (4.15-4.25 4H, complex spike); 6.81 (2H, d); And 6.95-7.40 (6H, complex spike).Embodiment 32 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-naphthyloxy) acrylate
Being similar to embodiment 6 described modes, when make triethyl 2-naphthyloxy phosphine acyl acetic acid ester and 4-(2-(and N-(2-benzoxazolyl)-N-methylamino-] during the ethoxy benzonitrile aldehyde reaction, gluey title compound is with the mixture segregation of 1: 1 double bond isomer. 1H NMR δ (CDCl 3) 1.02 and 1.15 (mixing 3H; OCH 2CH 3The triplet mark); 3.27 gentle 3.33 (mixing 3H, NMe) unimodal peak); (3.90 2H, complex spike); (4.05-30 4H, complex spike); And 6.75-7.80 (16H, complex spike).Embodiment 33
Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-naphthyloxy) propionic ester According to be similar to embodiment 25 described processing methodes by ethyl (E/Z) 3-[4-(2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-naphthyloxy) acrylate obtains the title compound of gluing form. 1H NMR δ (CDCl 3) 3.23 (2H, appd); 3.31 (3H, s); 3.70 (3H, s); 3.90 (2H, t); 4.21 (2H, t); 4.91 (1H, dd); 6.81 (2h, d), and 6.90-7.80 (13H, complex spike).Embodiment 34
3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-naphthyloxy) propionic acid
Figure C9310987400601
To be similar to embodiment 2 described modes by methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-naphthyloxy) propionic ester prepares title compound, mp162-4 ℃ (methyl alcohol).
1H NMR δ (DMSO-d 6) 3.17 (2H, complex spikes); 3.19 (3H, s); 3.87 (2h, t); 4.21 (2h, t); 5.03 (1H, dd); 6.85 (2H, d); (6.90-7.50 10H, complex spike); 7.72 (1H, d); 7.79 (2H, d); With 13.10 (1H, br use D 2The O exchange).Embodiment 35 ethyls (Z)-2-oxyethyl group-3-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl]-acrylate
Figure C9310987400611
Triethyl 2-oxyethyl group phosphine acyl acetic acid ester (3.44g) is dissolved in the anhydrous tetrahydro furan (25ml), under argon atmospher, this solution is slowly joined ice-cooled, the sodium hydride that stirred (60% dispersion in mineralizer oil; 0.56g) in the suspension in tetrahydrofuran (THF).At 0 ℃ mixture was stirred 30 minutes, adds 4-[2-[N-methyl-N-(2-pyridyl) amino afterwards] oxyethyl group] (3.29g) solution in tetrahydrofuran (THF) (30ml) of phenyl aldehyde (Eur.Patent Appl.Publication Number EP036228).To room temperature, stirred 22 hours on the limit with mixture heat, concentrates under vacuum then.Resistates is suspended in the water (300ml), and (2 * 300ml) extractions are with ethyl acetate solution water (500ml) and salt solution (500ml) washing that merges, dry [MgSO with ethyl acetate 4) and evaporation.With the glue of remnants on silica gel with 20% ethyl acetate chromatographic separation, make eluent with ethane, obtain the oily title compound.
Continue the mixture (referring to embodiment 36) that the washing chromatography column obtains comprising volume (Z)-irregular part and isomery (E)-alkene. 1H NMR δ (CDCl 3) 1-35 (6H, t); (3.14 3H, 3); (3.95 4H, complex spike); 4.21 (2H, t); 4.28 (2H, q); (6.50 2H, complex spike); 6.88 (2H, d); 6.95 (1H, s); (7.44 1H, complex spike); 7.72 (2H, d); With 8.15 (1H, compound honeybees).Embodiment 36 ethyls (E)-2-oxyethyl group-3-[4-[2-[N-methyl-N-[2-pyridyl) amino] oxyethyl group] phenyl)-acrylate
Figure C9310987400621
Will be from embodiment 35 the mixture chromatographic separation again of the double bond isomer that obtains of chromatography column, use 10% ethyl acetate specifically, make washing composition with ethane, at first wash-out volume (Z)-isomer then is required (E)-isomer, a kind of oil. 1H NMR δ (CDCl 3) 1.13 (3H, t); 1.40 (3H, t); 3.14 (3H, s); 3.90 (2H, q); 3.97 (2H, t); (4.15 4H, complex spike); 6.06 (1H, s); (6.55 2H, complex spike); 6.81 (2H, d); 7.10 (2H, d); (7.45 1H, complex spike); With 8.15 (1H, complex spikes).Embodiment 37 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2,2, the 2-trifluoro ethoxy) propionic ester
Figure C9310987400622
According to being similar to embodiment 1 described method, prepare gluey title compound by methyl 3-(4-hydroxyphenyl)-2-(2,2, the 2-trifluoro ethoxy) propionic ester. 1H NMR δ (CDCl 3) 3.00 (2H, complex spikes); 3.34 (3h, s); (3.65 1H, complex spike); 3.72 (3H, s); 3.94 (2H, t); (4.00 1H, complex spike); 4.15 (1H, dd); 4.24 (2H, t); 6.81 (2H, d); And 6.95-7.40 (6H, complex spike).
Mass spectrum (FAB, glycerine) shows MH +At 453.1647[C 22H 23F 3N 2O 3] H +Require 453.1637.Embodiment 38 methyl 2-oxyethyl groups-3-[4-[2-[N-methyl-N-[2-pyridyl) amino] oxyethyl group] phenyl]-propionic ester
Figure C9310987400631
According to being similar to embodiment 25 described methods by ethyl (Z)-2-oxyethyl group-3-[4-[2-[N-methyl-N-[2-pyridyl) amino] oxyethyl group] phenyl]-propionic ester prepares gluey title compound. 1H NMR δ (CDCl 3) 1.15 (3h, t); 2.93 (2H, d); 3.14 (3H, s); (3.33 1H, complex spike); (3.56 1H, complex spike); 3.69 (3H, s); (3.95 3H, complex spike); 4.15 (2H, t); (6.52 2H, complex spike); 6.81 (2H, d); 7.11 (2H, d); 7.42 (1H, dt); With 8.13 (1H, dd).
Embodiment 39 ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy-c acid esters
Figure C9310987400641
According to being similar to embodiment 8 described methods, make solvent with ethanol, by ethyl (E/Z) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy propylene acid esters prepares the oily title compound. 1H NMR δ (CDCl 3) 1.15 (3H, t); 1.22 (3H, t); 2.92 (2H, d); (3.33 1H, complex spike); 3.34 (3H, s); (3.55 1H, complex spike); (3.4 3H, complex spike); 4.15 (2H, q); 4.24 (2H, t); 6.80 (2H.d); And 6.95-7.40 (6H, complex spike).Embodiment 403-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-ethoxy-propionic acid
Figure C9310987400651
According to being similar to embodiment 2 described processing methodes by ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-oxyethyl group-propionic ester prepares title compound, mp109-110 ℃. 1H NMR δ (CDCl 3) 1.18 (3H, t); 2.98 (1H, dd); 3.04 (1H, dd); 3.32 (3H, s); (3.45 1H, complex spike); (3.61 1H, complex spike); 3.1 (2H, t); 4.04 (1H, dd); 4.18 (2h, t); 5.00 (1H, dr use D 2The O exchange); 6.80 (2H, d); And 6.95-7.40 (6H, complex spike).
Embodiment 413-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy-c acid amides
Figure C9310987400652
With oxalyl chloride and 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-solution of 2-ethoxy-propionic acid in methylene dichloride (5ml) refluxed 1.5 hours, and concentrated then.Resistates is dissolved in the methylene dichloride, stirred 30 minutes with ammoniacal liquor.After chloroform (* 4) extraction, that extraction liquid is dry and concentrated.Chromatographic separation (diethyl ether/methylene dichloride) obtains crystalline white foam from diethyl ether, m.p.=94-95 ℃. 1H?NMRδ(CDCl)1.12(3H,t?J=7)；2.85(1H,dd,J=14,7.5)；3.07(1H,dd,J=14,3.5)；3.35(3H,s)；3.37-3.55(2H,m)；3.87(1H,dd,J=7.5,3.5)；3.94(2H,t,J=5)；4.24(2H,t,J=5)；5.54(1H,brs)；6.43(1H,brs)；6.79(2H,d,J=8.5)；7.00(1H,dt,J=8.1)7.15(2H,d,J=8.5)；7.1-7.2(1H,m)；7.24(1H,dd,J=8.1)；7.36(1H,d,J=8.1)。
Embodiment 423-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-oxyethyl group thiopropionamide
Figure C9310987400661
With 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-oxyethyl group thiopropionamide (428mg, 1.1 moles) is suspended in toluene and adds Lawesson ' s reagent.Reflux after 3 hours, with suspension cooling and pour in the water.After chloroform (* 3) extraction, use the ammonia scrubbing extraction liquid, dry and concentrated.Chromatographic separation (ethanol/methylene) obtains white solid product, mm.p.=46-48 ℃. 1H?NMRδ(CDCl 3)1.14(3H,t,J=7)；2.91(1H,dd,J=14.7)；3.25(1h,dd,J=14.3)；3.35(3H,s)；3.35-3.51(2H,m)；3.94(2h,t,J=50；4.24(2H,t,J=5)；4.30(1H,dd,J=7,3.5)；6.79(2H,d,J=8.5)；7.01(1H,appt,J=7.5)；7.16(2H,d,J=8.5)；7.13-7.2(1H,obs,m)；7.25(1H,d,J=7.5)；7.35(1H,d,J=7.5)；7.44(1H,brs)；7.72(1H,brs)。Embodiment 435-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 1-oxyethyl group] ethyl-1,2, the 4-triazole
With 3-(4-[2-[N-(2-benzoxazolyl)-N-methylamino-] ethoxyl phenenyl]-the solution heating of 2-ethoxy-c acid amides (0.562g, 1.5 moles) in dimethylformamide dimethyl acetal 1.5 hours to 120 ℃, cool off then and concentrate.Resistates is dissolved in the acetate (4ml), adds hydrazine hydrate (1.1eq).100 ℃ 1.5 little to after, with solution cooling, with the ethyl acetate dilution, water (* 2) and sodium hydrogen carbonate solution washing with solution dry and concentrated after, with resistates chromatographic separation (ethanol/methylene).Obtain white solid product, m.p.=127-129 ℃.
1H?NMRδ(CDCl 3)1.13(2Hm,t,J=7)；3.09(2H,dq.J=16.6)；3.31(3H,s)；3.46(2H,q,J=7)；3.89-3.95(2H,m)；4.20(2H,t,J=5)；4.75(1H,dd,J=6.5,5.5)；6.72(2H,d,J=8.5)；6.96(2H,d,J=8.5)；7.01(1H,dt,J=8.1)；7.16(1H,dt,J=8.1)；7.26(1H,?dd,J=8.1)；7.33(1H,dd,J=8.1)；8.00(1h,s)。
Embodiment 445-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 1-oxyethyl group] ethyl-1,2, the 4-oxadiazole
Figure C9310987400681
Will be at 3-[4-[2-[N-(2-the benzoxazolyl)-N-methylamino-in the dimethylformamide dimethyl acetal (0.6ml, 4.6 moles)] oxyethyl group] phenyl]-2--ethoxy-c acid amides (0.7g, 1.8 moles) heating 1.5 hours to 120 ℃.After the cooling resistates concentrated and dissolve in 70% acetic acid aqueous solution (2cm 3) in.In this solution, add 5N potassium hydroxide (0.44m) and hydroxyl hydrochloride (152mg), stirred then 15 minutes.Behind the dilute with water,, extraction liquid is washed with water dry (MgSO with methylene dichloride (* 2) extractive reaction thing 4) and concentrate.Resistates is dissolved in Glacial acetic acid/diox (2/2ml).Heated 1 hour to 90 ℃.Behind the dilute with water,,, dry and concentrated with extraction liquid water (* 2) washing with chloroform (* 3) extraction product.Chromatographic separation (diethyl ether/hexane) obtains yellow solid product, m.p.=89-90 ℃.
1H?NMRδ(CDCl 3)1.16(3H,t,J=7)；3.14(1H,q,J=14)；3.18(1H,q,J=14)；3.34(3H,S)；3.40-3.56(2H,m)；3.94(2h,t,J=5)；4.23(2H,t,J=5)；4.75(1H,dd,J=8.6)；6.79(2H,d,J=9；7.00(1H,dt,J=7.5)；7.07(2H,d,J=90；7.16(1H,dt,J=7.5,1)；7.31(1H,dd,J=7.5?0.5)；7.35(1H,dd,J=7.5,0.5)；8.37(1H,s)。
Embodiment 45 mapping enhanced methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-s] oxyethyl group] phenyl]-2-methoxy propyl acid esters
Figure C9310987400691
Will be in deionized water (380ml) lipase (from Rhizopus delemar, 680mg exBiocatalysisLtd) stirs and the PH of mixture is transferred to 7.0.In this mixture, add racemic methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-in room temperature (23 ℃)] oxyethyl group] phenyl]-solution of 2-methoxy propyl acid esters (1g) in acetone (20ml).The reaction mixture that stirring obtains is by keeping PH 7.0 with the automatic titration of 0.1M sodium hydroxide solution.After joining the alkali of 66% molar equivalent in the reactant, add hydrochloric acid, make solution to PH2.0, product is extracted in the methylene dichloride, remove the extraction liquid acid product of organic phase with 50% saturated sodium bicarbonate, water washing, dry (sal epsom) organic phase, obtain during evaporation 350mg oily methyl (3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-methoxy propyl acid esters, measure to determine that by chirality HPLC the enantiomorph ratio is 5: 95., be extracted into again in the methylene dichloride alkaline aqueous extraction liquid acidifying with hydrochloric acid, after drying and the evaporation, obtain 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxypropionic acid, a kind of white solid.In room temperature this acid in methyl alcohol was stirred 3 hours, with HCl with its presaturation, reclaim methyl 3-[4-[2-[N-(2-the benzoxazolyl)-N-methylamino-that produces by extraction] oxyethyl group] phenyl]-2-methoxy propyl acid esters, the enantiomorph ratio of being measured by HPLC is 70: 30.Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-enantiomorph of 2-methoxy propyl acid esters is than determining by HPLC, on chirality AGP post with 12% acetonitrile wash-out, in the sodium dihydrogen phosphate (PH7.0) of 0.01M, and by UV monitor (at 245nm) mensuration product.Enantiomorph is than quoting from the wash-out level.Embodiment 46 (+)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxy acrylic acid
Figure C9310987400711
Lipase (the 300mg of Rhizopus delemar will be derived from, ex BiocatalystLtd.) (125ml) stirs in deionized water, the pH value of this mixture is adjusted to 7.0, at room temperature (23 ℃) add methyl 3-[4-[2-[N-(2-the benzoxazolyl)-N-methylamino-that is dissolved in acetone (5ml) to this mixture] oxyethyl group] phenyl]-2-methoxy propyl acid esters (690mg) (enantiomeric ratio 8: 92, as in the example 1 preparation) solution, the reaction mixture that generates is at room temperature stirred, make pH value remain on 7.0 with the automatic titration of 0.1M sodium hydroxide solution, finish up to hydrolysis.The 0.1M sodium hydroxide solution is added, make the PH of this reaction mixture reach 95, after this use dichloromethane rinse, water is acidified to PH1 with spirit of salt, in methylene dichloride, washing, dry (sal epsom) also evaporate with acid extraction, the solid that generates are obtained (+) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-of 490mg with the hexane development] oxyethyl group] phenyl]-2-methoxy propionic acid, be white solid, m.p.121-123 ℃; Enantiomeric ratio 92.8 (measuring) by HPLC; [α] D 25+ 13 °, MeOH, C0.5.3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-determination of ratio of the enantiomorph of 2-methoxy propionic acid be by with the HPLC method on a chirality AGP post,, monitor at the 245nm place to detect product at 0.01M sodium hydrogen phosphate solution (PH=7.0) with 4.8% acetonitrile with UV.The ratio of enantiomorph is reflected successively according to eluotropic series.Embodiment 47 (-)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxypropionic acid
Figure C9310987400721
To derive from Rhizopus, delemar (500mg, ex Biocatalysts Ltd.) lipase stirs in deionized water (380ml), the pH value of this mixture is adjusted to 7.0, adds methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-under room temperature (23 ℃) in this mixture] oxyethyl group] phenyl]-2-methoxy propyl acid esters (950mg) (preparation is reclaimed by heavy esterification acid in as example 1) is at the solution of acetone (20ml).The mixture of this generation at room temperature stirs, is 7.0 by automatic dropping 0.1M sodium hydroxide solution to keep pH value, alkali up to 32% molar equivalent is added in the reactant, add spirit of salt then, make that solution PH is 2.0, product is extracted in the methylene dichloride, saturated solution of sodium bicarbonate extracted organic phase with 50%, remove acid product and water, washing, drying (sal epsom) organic phase,, then make the recovery ester of 543mg through evaporation, this water with hcl acidifying to PH1, acid is extracted in the methylene dichloride, through washing, and dry (sal epsom) and evaporation.The solid that obtains thus obtains (-) 3-[4-[2-[N-(2-the benzoxazolyl)-N-methylamino-of the white solid of 256mg with the hexane development] oxyethyl group] phenyl]-the 2-methoxypropionic acid; M.p.116-119 ℃; Enantiomeric ratio 7: 93 (measuring) by HPLC, [α] D 25-10 °, MeOH, CO.55.Measuring enantiomeric ratio by the HPLC method narrates in example 46.Embodiment 48 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxyphenyl]-2-ethoxy propylene acid esters When the same 4-[2-[N-of triethyl 2-oxyethyl group phosphono acetic ester (the 2-benzoxazolyl]-the N-methylamino-] oxyethyl group]-when the 2-methoxybenzaldehyde reacts in the mode that is similar among the embodiment 6 record; this title compound, the form of double bond isomer mixture that can be a kind of 66: 34 for a kind of colloid obtains. 1H NMR δ (CDCl 3) 1.09 and 1.25-1.45 (bonded, 6H, CH 2CH 3Triplet); 3.35 (3H, s); 3.75 and 3.80 (bonded 3H, OMe one heavy peaks); (3.87-4.40 8H, complex spike); (6.06 0.34H, E-alkene one heavy peak) and 6.40-8.18 (7.66H, complex spike, aromatic protons and Z-alkene).Embodiment 49 ethyls-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group]-the 2-methoxyphenyl]-2-ethoxy-c acid esters
Figure C9310987400732
This title compound, being glue is from ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-methoxyphenyl]-2-ethoxy propylene acid esters is with the method preparation of record the similar embodiment 8. 1H NMR δ (CDCl 3) 1.10-1.40 (6H, complex spike); (2.94 2H, complex spike); 3.34 (3H, s); (3.35 1H, complex spike); (3.55 1H, complex spike); 3.76 (3H, s); 3.93 (2H, t); 4.10 (1H, dd); 4.13 (2H, q); 4.24 (2H, t); (6.39 2H, complex spike) and 6.95-7.40 (5H, complex spike).Embodiment 50 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy acrylate
Figure C9310987400741
When the same 4-[2-[N-of triethyl 2-tert.-butoxy phosphine acyl acetic acid ester (2-benzoxazolyl)-N-methylamino-] oxyethyl group] when phenyl aldehyde reacts to be similar to the mode of implementing 6 records; this title compound (jelly) then makes with the form of 76: 24 mixtures of Z and E key isomer. 1H NMR δ (CDCl 3) 1.18 and 1.35 (bonded 3H, OCH 2CH 3The triplet mark); 1.27 and 1.34 (bonded 9H, OBu t-heavy peak); 3.34 and 3.35 (bonded 3H, the heavy peaks of NMe-); (3.95 2H, complex spike); (4.10-4.28 4H, complex spike); (6.53 0.24H, s, E-alkene) and 6.75-7.80 (8.76H, complex spike, Z-alkene and aromatics proton).
Embodiment 51
3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy propionic ester
Figure C9310987400751
This title compound (being jelly) is from (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy acrylate uses with the similar approach that is recorded in embodiment 25 and prepares, the methyl ester that this material is corresponding with some mixes, and this mixture can directly be used in down and need not purifying in the step. 1H NMR δ (CDCl 3) 0.91 (9H, s); 1.24 (3H, t); (2.85 2H, complex spike); 3.34 (3H, s); 3.93 (2H, t); 4.03 (1H, dd); 4.16 (2H, q); 4.23 (2H, t); 6.79 (2H, d); And 6.95-7.40 (6H, complex spike).Embodiment 523-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy propionic acid
Figure C9310987400761
This title compound (being jelly) is from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy propionic ester to be to be similar to the embodiment 2 the method preparation of record. 1H NMR δ (CDCl 3) 1.04 (9H, s); 2.84 (1H, dd); 2.98 (1h, dd); 3.34 (3H, s); 3.93 (2H, t); 4.13 (1H, dd); 4.21 (2H, t); 6.79 (2H, d); 6.95-7.40 (6H, complex spike) and 7.45 (1H, broad peak is with D 2The O exchange).Embodiment 533-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-tert.-butoxy propionic acid, sodium salt (60% is scattered in the mineral oil with sodium hydride, 50mg) join once stirring, the 3-[4-[2-[N-of ice-cold mistake (2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-solution of 2-tert.-butoxy propionic acid (0.496g) in methyl alcohol (10ml) in, this mixture was stirred 10 minutes down at 0 ℃, vacuum concentration is also used ether (40mL) redilution, the solid that is generated then obtains title compound with drying after filtration, mp＞250 ℃. 1H NMR δ (DMSO-d 6) 0.85 (9H, s); 2.43 (1H, dd); 2.73 (1H, dd); 3.21 (3H, s); 3.55 (1H, dd); 3.86 (2H, t); 4.19 (2H, t); 6.77 (2H, d) and 6.95-7.40 (6H, complex spike).Embodiment 54 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-phenyl ethoxy) acrylate This title compound (being made of 71: 29 double bond isomer mixtures) is to adopt from triethyl 2-(2-benzene oxyethyl group) phosphine acyl acetic acid ester to be similar to method preparation that embodiment 6 narrates. 1H NMR δ (CDCl 3) 1.14 and 1.34 (bonded 3H, OCH 2CH 3, the triplet mark); (3.05 2H, complex spike); 3.33 and 3.34 (bonded 3H, NMe marks); (3.95-4.80 8H, complex spike); (6.07 0.29H, E-alkene-weight peak) and 6.07-7.55 (13.71H, complex spike, Z-alkene and aromatics proton).Embodiment 55 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-benzene oxyethyl group) propionic ester
Figure C9310987400781
This title compound (jelly) is from ethyl (E/Z) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-make with the method that is similar among the embodiment 2 record 2-(2-phenyl ethoxy) acrylate. 1H NMR δ (CDCl 3) 2.84 (2H, t); (2.93 2H, complex spike); 3.34 (3h, s); (3.43 1H, complex spike); 3.68 (3H, s); (3.77 1H, complex spike); (3.94 3H, complex spike); 4.23 (2H, t); 6.77 (2h, d); And 6.95-7.40 (11H, complex spike).Embodiment 563-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-phenyl ethoxy) propionic acid
Figure C9310987400791
This title compound, m.p131-3 ℃ (methylene dichloride-hexane) is from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-phenyl ethoxy) propionic ester by being similar to the method preparation of embodiment 2 records. 1H NMR δ (CDCl 3) 2.95 (2H, t); 2.93 (1H, dd); 3.04 (1H, dd); 3.32 (3H, s); (3.57 1H, complex spike); (3.77 1H, complex spike); 3.91 (2H, t); 4.02 (1H, dd); 4.17 (2H, d); 6.10 (1H, broad peak is with D 2The O exchange); 6.77 (2H, d) and 6.95-7.40 (11H, complex spike).Embodiment 57 ethyls (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methoxy ethoxy) acrylate
Figure C9310987400792
This title compound (jelly) uses from triethyl 2-(2-methoxy ethoxy) phosphine acyl acetic acid ester and is similar to the method for narrating among the embodiment 6 and makes, and is 76: 24 double bond isomer mixture. 1H NMR δ (CDCl 3) 1.12 and 1.35 (bonded 3H, OCH 2CH 3Triple honeybees); (3.35-3.45 bonded, 6H, complex spike NMe and OMe singlet); 3.67 and 3.72 (bonded 2H, complex spike, OCH 2CH 2The OMe mark); (3.90-4.35 8H, compound honeybee); (6.15 0.24H, E-alkene singlet) and 6.80-7.80 (8.76H, complex spike).Embodiment 58 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2-methoxyethoxy) propionic ester
Figure C9310987400801
This title compound (jelly) is from ethyl (E/Z) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-make with the method that is similar to embodiment 25 2-(2-methoxy (ethoxy)) acrylate. 1H NMR δ (CDCl 3) 2.95 (2H, complex spikes); 3.29 (3H, s); 3.34 (3H, s); (3.47 3H, compound honeybee); (3.68 1H, complex spike); 3.69 (3H, s); 3.93 (2H, t); 4.06 (1H, dd); 4.23 (2H, t); 6.79 (2H, d); And 6.95-7.40 (6H, complex spike).Embodiment 59 methyl (Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-carboxymethoxyl) acrylate
Figure C9310987400811
Will (60% be scattered in the mineral oil by sodium oxide, 0.30g), diglycollic acid dimethyl ester (0.81g) and 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl aldehyde (2.22g) formed mixture in dried benzene (50mL) at room temperature stirs a whole night.Add acetate (1mL) in wherein, this mixture is poured in the frozen water, and uses ethyl acetate extraction.This bonded ethyl acetate layer washes with water, dry (MgSO 4) and evaporation.On silicagel column, be used in the methylene dichloride 2% methyl alcohol the oily matter of this generation is carried out chromatographic separation, then product crystallization from ethyl acetate, m.p111-112 ℃. 1H NMR δ (CDCl 3) 3.34 (3H, s); 3.83 (3H, s); 3.95 (2H, t); 4.25 (2h, t); 4.51 (2H, t); (6.85-7.50 9H, complex spike) and 9.40 (1H, broad peak are used D 2The O exchange).Embodiment 60 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-carboxymethoxyl) propionic ester
Figure C9310987400821
This title compound, m.p154-155 ℃, with methyl (Z)-3-[4-[2-(N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 2-carboxymethoxyl) acrylate is by making with being similar to the method that embodiment 8 describes. 1H NMR δ (CDCl 3) 2.95 (1H, dd); 3.09 (1H, dd); 3.31 (1H, s); 3.75 (1H, s); (3.93 2H, complex spike); 4.07 (2h, s); (4.20 3H, complex spike); 6.79 (2H, d); And 6.95-7.40 (7H, compound honeybee are used D through swaying 2O is reduced into 6H).Embodiment 615-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 1-ethoxyethyl group]-the 3-methyl isophthalic acid, 2, the 4-oxadiazole This title compound, the method for record is similar among mp61-62 ℃ preparation method and the embodiment 44, but different be to have replaced N with the N,N-dimethylacetamide dimethyl-acetal, the dinethylformamide dimethyl-acetal. 1H NMR δ (CDCl 3) 1.15 (3H, t); 2.39 (3H, s); 3.12 (1h, q); 3.14 (1H, q); 3.35 (3H, s); 3.35-3.60 (2H, m); 3.94 (2H, t); 4.23 (2H, t); 4.65 (1h, dd); 6.79 (2H, d); And 7.00-7.36 (6H, complex spike).Embodiment 625-[2-[4-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-the 1-ethoxyethyl]-1 ', 2,3,4-(1H)-tetrazolium
Figure C9310987400831
Heavy-hydrogenated sodium (0.76g) and trimethylsilyl chloride (1mL) are joined 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy propionitrile (0.85g), at N, in the solution of dinethylformamide (30mL).This mixture was refluxed 4 days, and cooling in the impouring water, and extracts with ethyl acetate.This bonded ethyl acetate layer washes with water, dry and evaporation.Debris is made solvent with 1% methyl alcohol that is dissolved in ether by chromatography and is then obtained this title compound on silicagel column, foam is white in color. 1H NMR δ (CDCl 3) 1.13 (3H, t); 3.13 (2H, dd); 3.22 (3H, s); 3.51 (2H, dq); 3.88 (2H, t); 4.15-4.20 (2H, m); 4.99 (1H, t); 6.22 (2H, d); 6.80 (2H, d); 7.04 (1H, dt); 7.16 (1H, dt); And 7.25-7.31 (2H, m).Step 1 ethyl 3-(4-hydroxyphenyl) 2-methoxy propyl acid esters In 30 minutes with 2-diazo-3-(4-hydroxyphenyl) ethyl propionate (c.f.N Takamura and T.Mzoguchi, Tetrahedron Lett, 1971,4495) (8.8g) solution in benzene (40mL) joins vinegar ester rhodium (II) dipolymer (10mg) of the backflow through stirring, in the mixture of methyl alcohol (7.9mL) and benzene (50mL),, make it be cooled to room temperature a whole night then to this mixture reflux 30 minutes again, and water (2 * 200mL) washing, with benzole soln drying (MgSO 4) and evaporation, residual oil body is the chromatogram separated secondary on silicagel column, makes elutriant with 20% ethyl acetate that is dissolved in the hexane for the first time, makes elutriant with the ethyl acetate that is dissolved in 4% in the methylene dichloride then and then obtains a kind of buttery title compound.
1H NMR δ (CDCl 3) 1.22 (3H, t); 2.94 (2H, d); 3.35 (3H, s); 3.94 (1H, t); 4.20 (2H, q); 5.73 (1H uses D 2The O exchange); 6.75 (2H, d); With 7.15 (2H, d).
Step 23-(4-hydroxyphenyl)-2-methoxy methyl propionate
Figure C9310987400851
In 10 minutes with 2-diazo-3-(4-hydroxyphenyl) methyl propionate (of Tetrahedron lett, 1971; 4495) (8.58g) solution in methyl alcohol (120mL) joins in room temperature and nitrogen atmosphere in the mixed solution of rhodium acetate (II) dipolymer (0.18g) in methyl alcohol (50mL), with the mixture reflux of this generation 5 hours, left standstill under the room temperature then 15 hours, according to vacuum concentration, debris is dissolved in the ethyl acetate (500mL), water (3 * 300mL) and salt solution (500mL) washing, dry (MgSO 4) and evaporation, the jelly of this generation then obtains title compound, mp61-3 ℃ carrying out chromatographic separation at the solution of 4% ethyl acetate to 6% ethyl acetate in methylene dichloride as eluant with concentration gradient on the silicagel column. 1H NMR δ (CDCl 3) 2.95 (2H, d); 3.40 (3H, s); 3.75 (3H, s); 4.00 (1H, t); 6.30 (1H, broad peak are used D 2The O exchange); 6.80 (2H, d); With 7.15 (2H, d).Step 3 (E/Z)-1-methoxyl group-2-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl] ethene Chlorination methoxymethyl triphenyl phosphorus (12.34g) is suspended in the dry tetrahydrofuran (200mL), is cooled to-10 ℃ and in 5 minutes, is under the nitrogen atmosphere to stir and adds the diisopropyl amide lithium (2.0M is in normal heptane/tetrahydrofuran (THF)/ethylbenzene; 13.5mL in) solution, the mixture of this generation is warmed to 10 ℃, under this temperature, stirred 1 hour, with 4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] (4.60g) adding under 10 ℃ of the solution in dry tetrahydrofuran (75ml) of phenyl aldehyde (European patent application publication No. 0306228).Stirred this mixture under the room temperature 4.5 hours then, evaporating solvent, debris are suspended in the water (600mL), with dichloromethane extraction (3 * 250mL), to this with dichloromethane solution water of merging (3 * 1L) and salt solution (1L) washing, drying (MgSO 4) and evaporation.This debris is used in 1.5% in the methylene dichloride on silicagel column methyl alcohol carries out chromatographic separation as elutriant and then obtains this title compound, is jelly, is 1: 1 double bond isomer mixture. 1H NMR δ (CDCl 3) (Z)-alkane:3.12 (3H, s); 3.72 (3H, s); 3.94 (2H, t); 4.14 (2H, t); 5.14 (1H, d, J=7.0Hz); 6.01 (1H, d, J=7.0Hz); (6.48 2H, complex spike); 6.80 (2H, d); 7.11 (2H, d); (7.45 1H, complex spike); With 8.15 (1H, dd).(E)-and alkene:3.12 (3H, s); 3.63 (3H, s); 3.94 (2H, t); 4.15 (2H, t); 5.74 (1H, d, J=12.91Hz); (6.49 2H, complex spike); 6.80 (2H, d); 6.88 (1H, d, J=12.9Hz), 7.45 (3H, complex spikes); With 8.15 (1H, dd).Step 41,1-dimethoxy-2-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl] ethane Will be by (E/Z)-1-methoxyl group-2-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl ethene (2.80g), the mixture that P-toluenesulphonic acids monohydrate (1.90g) and methyl alcohol (150mL) are formed heated 20.75 hours under refluxing, and cooling is evaporation also.Debris is dissolved in the ethyl acetate (200mL), with saturated sodium bicarbonate solution (200mL) and salt solution (200mL) wash, dry (MgSO 4) and evaporation.This gelationus title compound need not passivation and just can use in next step. 1H NMR δ (CDCl 3) 2.85 (2H, d); 3.15 (3H, s); 3.33 (6H, s); 3.98 (2H, t); 4.20 (2H, t); 4.49 (1H, t); (6.50-7.50 7H, compound); 8.20 (1H, dd); Step 52-methoxyl group-3-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl] propionitrile
Figure C9310987400872
At room temperature cyaniding trimethyl silicane (3.4mL) is added drop-wise to by 1 1-dimethoxy 2-[4-[2-[N-methyl-N-(2-pyridyl) amino] oxyethyl group] phenyl] and ethane (2.64g) methylene dichloride (70mL) by the solution of forming in.Stirred solution in adding etherate of trifluoroboron (0.3mL) process at room temperature continues to stir 1.5 hours, and then adds other a part of etherate of trifluoroboron (1mL).Dilute this mixture with methylene dichloride (100mL) after 2 hours, and with saturated sodium hydrogen carbonate solution (2 * 300mL), water (2 * 300mL) and salt solution (300mL) washing, dry (MgSO 4) and evaporation.1% methyl alcohol carries out chromatographic separation as elutriant in the methylene dichloride with being dissolved on silicagel column with debris, then gets this title compound, is jelly, need not further purification and just can use. 1H NMR δ (CDCl 3) 3.04 (2H, d); 3.14 (3H, s); 3.46 (3H, s); 3.96 (2H, t); (4.16 3H, compound); (6.55 2H, compound); 6.84 (2H, d); 7.15 (2H, d); 7.45 (1H, td) and 8.15 (1H, dd).Step 6 methyl 2-amino-3-[4-[2-[N-(2-benzoxazole)-N-methylamino-] oxyethyl group] phenyl] propionic ester
Figure C9310987400881
Sodium-chlor 160% is scattered in the oil; Be dissolved in dried N 1.00g under nitrogen atmosphere, be added drop-wise in batches, in the solution through stirring of the cruel propylhomoserin trimethyl (3.90g) of dinethylformamide (70mL), stirred 30 minutes under this mixture room temperature, add 2-[N-(2-benzoxazolyl)-N-methylamino-then] the ethanol methylsulfonyl ester (N that european patent application specification sheets (0006228) (5.90g) is being done, the solution that N-dimethylformamide (30mL) forms, this mixture was heated 6 hours down at 100 ℃, cooling, water (500mL) dilution and with the extracting of acetate ethanol, with ethyl acetate layer salt solution (2 * 1L) washings, the dry (MgSO that merges 4) and evaporation.This debris is carried out chromatographic separation with 5% methyl alcohol in the methylene dichloride as elutriant on silicagel column, then obtain a kind of oily matter, and the crystallization from ethyl acetate of this material then obtains title compound, mp95-6 ℃. 1H NMR δ (CDCl 3) 1.45 (2H, br use D 2The O exchange); 2.81 (1H, dd); 3.01 (1H, dd); 3.33 (3H, s); 3.67 (1H, dd); 3.70 (3H, s); 3.95 (2H, t); 4.25 (2H, t); 6.83 (2H, d); And 6.95-7.40 (6H, compound).Step 7 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-two azo propionic esters
Figure C9310987400891
To by 2-amino-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] mixture formed of methyl propionate, acetate (4.4mL) and chloroform (160mL) drips with Isopentyl nitrite (3.2mL) and handles.This mixture reflux 1.5 hours, cooling, with chloroform (200mL) dilution and is used dilute hydrochloric acid (200mL) successively, water (2 * 200mL) and salt solution (200mL) wash, this chloroformic solution is at MgSO 4Last dry, evaporation is carried out chromatographic separation with 3% ethyl acetate in the methylene dichloride as elutriant with debris then on silicagel column, then obtain this title compound, jelly. 1H NMR δ (CDCl 3) 3.34 (3H, s); 3.56 (2H, s); 3.77 (3H, s); 3.94 (2h, t); 4.25 (2H, t); And 6.80-7.40 (8H, compound).Step 83-(4-hydroxyphenyl) 2-isopropoxy methyl propionate
Figure C9310987400901
This gelationus title compound is to prepare by the method that is similar to step 2 record from 2-two azos-3-(4-hydroxyphenyl) methyl propionate (3.00mg). 1H NMR δ (CDCl 3) 0.97 (3H, d); 1.14 (3H, d); (2.91 2H, compound); (3.51 1H, compound); 3.71 (3H, s); 4.05 (1H, dd); 6.02 (1H, br use D 2The O exchange); 6.75 (2h, d); With 7.08 (2H, d).Step 93-(4-hydroxyphenyl)-2-propoxy-methyl propionate
Figure C9310987400902
This buttery title compound is to prepare by the method that is similar to step 2 from 2-two azos-3-(4-hydroxyphenyl) methyl propionate (2.56g). 1H NMR δ (CDCl 3) 0.83 (3H, t); (1.54 2H, compound); 2.93 (2H, app.d); (3.22 1H, compound); (3.51 1H, compound); 3.71 (3H, s); 3.99 (1H, t); 5.54 (1H, br use B 2The O exchange); 6.74 (2H, d); With 7.08 (2H, d).Step 102-hydroxyl-3-(4-hydroxyphenyl) methyl propionate With 3-(4-benzyl oxy phenyl)-2-ethylene-lactic acid methyl esters (referring to international patent application prospectus publication number WO9101337) (5.72g) solution in methyl alcohol (120mL) under nitrogen atmosphere, join 10% by in the ice-cooled suspension of palladium charcoal (1.90g) in methyl alcohol (30mL).Solid formic acid ammonium (6.4g) is added wherein, and this mixture heating up was refluxed 15 minutes, be cooled to room temperature then.Pass this reaction mixture of diatomite filtration and remove catalyzer.With debris be suspended in dilute hydrochloric acid (2M, 100mL) in, then with ethyl acetate (2 * 400mL) extractions.With the ethyl acetate solution water (400mL) that merges, salt solution (400mL) washing, dry (MgSO 4) and evaporation, last jelly is used in 1.5% methyl alcohol in the methylene dichloride carries out chromatographic separation as elutriant and then obtain this title compound, mp42-43 ℃ on silicagel column. 1H NMR δ (CDCl 3) 2.85 (1H, broad peak are used D 2The O exchange); 2.90 (1H, dd); 3.05 (1H, dd); 3.77 (3H, s); 4.42 (1H, m is through using D 2O washing post shrinkage is to dd); 5.36 (1H, broad peak are used D 2The O exchange); 6.70 (2H, d); With 7.05 (2H, d).Step 113-(4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethylene-lactic acid methyl esters This title compound, mp109-112 ℃ is to be prepared by the step that is similar to the EXAMPLE l description from 2-hydroxyl-3-(4-hydroxyphenyl) methyl propionate. 1H NMR δ (CDCl 3) 2.68 (1H, d use D 2The O exchange); 2.90 (1H, dd); 3.05 (1h, dd); 3.35 (3H, s); 3.76 (3H, t); 3.95 (2H, t); 4.41 (1H, m is through using D 2O wash shrinkage dd); 6.81 (2H, d); And 6.95-7.40 (6H, compound).Step 122-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] methyl acetate (60% is scattered in the mineral oil, 2.20g) is added to the 4-hydroxyphenyl methyl acetate (8.30g) that stirred at the N that does, in the solution of dinethylformamide (100mL) under room temperature and nitrogen atmosphere in batches with sodium hydride.Under this temperature, this mixture was stirred 30 minutes, adding 2-[N-(2-benzoxazolyl)-N-methylamino-then] ethanol methylsulfonyl ester (13.50g) is at N, solution in the dinethylformamide (150mL), this mixture was heated 18 hours down at 80 ℃, cooling and vacuum concentration, debris water (1L) dilution, with ethyl acetate (3 * 400mL) extractions, the ethyl acetate solution water that then is combined (4 * 1L), salt solution (1L) washing, dry (MgSO 4) and evaporation.This debris is used in 1.5% methyl alcohol in the methylene dichloride on silicagel column carries out chromatographic separation as elutriant and then can obtain title compound, is a kind of jelly, need not to be further purified and is used. 1H NMR δ (CDCl 3) 3.35 (3H, s); 3.57 (2H, s); 3.70 (3H, s); 3.93 (2H, t); 4.28 (2H, t); And 6.85-7.45 (8H, compound).Step 132-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] ethanol
Figure C9310987400931
With 2-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] and the solution of methyl acetate (11.60g) in the ether (200mL) of dry state gently join in the nitrogen atmosphere ice-cooled, be dissolved in ether 150mL through what stir) in the suspension of lithium aluminium hydride in.Stirred this mixed solution 20 minutes down at 0 ℃, then carefully with water (10mL) and oxygen chloric acid (2M; 10mL) be added drop-wise to wherein.This mixture water (200mL) dilution is adjusted to PH4.0 with solution, uses ethyl acetate (3 * 200mL) extractions then.With the ethyl acetate solution water that merges (2 * 500mL), salt solution (500mL) washing, dry (MgSO 4) and the evaporation then obtain title compound, mp95-97 ℃. 1H NMR δ (CDCl 3) 2.15 (1H, uses D at broad peak 2The O exchange); 2.75 (2H, t); 3.30 (3H, s); 3.80 (2H, t); 3.97 (2H, t); 4.22 (2H, t); And 6.80-7.45 (8H, compound).Step 144-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl acetaldehyde
Figure C9310987400941
Pyridine-sulphur trioxide mixture (1.53g) is joined under nitrogen atmosphere through stirring at the solution of methyl-sulphoxide (5mL), ice-cooled by 2-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] ethanol (1.00g), in the mixture that triethylamine (2.25mL) and methylene dichloride (30mL) are formed.Down stirred this mixture 10 minutes at 0 ℃, stirred 5 hours under the room temperature then, use methylene dichloride (100mL) dilution then, and successively water (2 * 100mL), hydrochloric acid (0.5M; 100mL), water (2 * 100mL) and salt solution (100mL) washing, dry (MgSO 4) and evaporation.This debris is used in 5% ethyl acetate that methylene dichloride does in the solvent and then obtains title compound through chromatographic separation, a kind of jelly on silicagel column. 1H NMR δ (CDCl 3) 3.29 (3H, s); 3.53 (2H, d); 3.86 (2H, t); 4.19 (2H, t); (6.80-7.50 8H, compound); With 9.68 (1H, t).Step 153-(4-hydroxyphenyl)-2-(2,2, the 2-trifluoro ethoxy) methyl propionate
Figure C9310987400951
Under room temperature and nitrogen atmosphere with 2-two azos-3-(4-hydroxyphenyl) methyl propionate (3.00g) 2,2, the solution of 2-trifluoroethanol (10ml) joined acetic acid rhodium (II) dipolymer (0.0064g) and 2 through stirring in 15 minutes, 2, in the mixture that 2-trifluoroethanol (5mL) is formed, stirred this mixture 15 minutes under the room temperature, reflux is 4 hours then, cooling and evaporation.This debris is used in 4% ethyl acetate in the methylene dichloride on silicagel column carries out chromatographic separation as eluant and then obtains this title compound, a kind of jelly, and it need not to purify and then can use.
1H NMR δ (CDCl 3) 3.00 (2H, compound); (3.65 1H, compound); 3.74 (3H, s); (4.00 1H, compound); 4.17 (1H, dd); (5.20 1H, broad peak exchange with D2O); 6.75 (2H, d); With 7.08 (2H, d).Mass spectrum (EI) is expressed M at the 278.0763amu place +C 12H 13F 3O 4Theoretical value be 278.07666.Step 163-4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-ethoxy propionitrile
Figure C9310987400961
Will be by 4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenylacetic aldehyde (1.5g), the mixture reflux that P-toluenesulphonic acids monohydrate (100mg), 3A molecular sieve (2g) and ethanol (30ml) are formed 18 hours, cool off, also stirred 30 minutes with salt of wormwood (5g), this mixture is passed diatomite filtration and evaporation, then obtain 3-4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl] acetaldehyde two propionic aldehyde, this material need not to purify and just can use (following).
Etherate of trifluoroboron (0.05ml) is joined by above-mentioned propionic aldehyde (1.5g) with in methylene dichloride (20mL) in the cyaniding trimethyl silicane cold soln (4 ℃).Warm this mixture arrives room temperature, and stirs 24 hours, then it is poured in the aqueous solution of sodium bicarbonate, and this organic phase is through separation, dry (MgSO 4) and evaporation.Debris then makes this buttery title compound using 20% ether in methylene dichloride to carry out chromatographic separation as eluant on the silicagel column.
1H NMR δ (CDCl 3) 1.20 (3H, t); 3.05 (2H, d); 3.30 (3H, s); (3.3-4.8 2H, compound); 3.87 (2H, t); (4.10-4.30 3H, compound); 6.82 (2H, d); And 6.q0-7.40 (6H, compound).The usefulness obesity mice of proof compound, the oral glucose tolerance experiment is fed with Powdered oxoid regulation food (ob/ob) mouse of C57611/6 hypertrophy.Through after at least one week, these mouse continue to feed according to pulverous oxoid recipe, or feed and give the Powdered oxoid food that contains testing compound.Through 8 days according to after the diet of the amount of augmenting, all fasting 5 hours of all mouse, the glucose of intake dosing (3g/kg) then.Sampling behind the blood sample that is used for glucose analysis 0,45,90 and 135 minutes after taking glucose, the gained result is shown in the following table with the minimizing of the area blood glucose curve under percentile scale, and wherein the treatment group of testing compound and control group compare.The each processing with eight mouse.
Content embodiment (μ mo1.kg below the table blood glucose curve in the food -1Of diet) the long-pending percentage % 1 3,000 54 30 49 2 3,000 51 30 58 3 100 53 4 300 55 30 49 5 100 51 6 1,000 50 30 26 9 100 49 10 100 53 10 56 11 100 51 30 49 14 30 54 17 100 52 20 100 58 23 100 58 26 100 51 29 100 60 30 55 31 30 41 34 100 36 35 1,000 59 37 30 61 38 10 56 40 10 62 that reduces
Content embodiment (μ mol.kg below table (continuing) blood glucose curve in the food -1Of diet) the long-pending percentage %41 30 6,142 30 6,943 100 5,644 300 3,746 30 5,747 30 6,149 30 5,361 10 37 that reduces

Claims (4)

1. the compound shown in the formula I, or its tautomeric forms or its pharmaceutical salts, or its medicinal solvent thing, said formula I is:
Figure C9310987400021
Wherein, A 1Be 2-pyridyl or 2-benzoxazolyl;
R 2Represent OR 3, R wherein 3Be hydrogen or C 1-6Alkyl.
2. according to the compound of claim 1, this compound is 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino-] oxyethyl group] phenyl]-2-(2,2, the 2-trifluoro ethoxy) propionic ester; Or its pharmaceutical salts or its medicinal solvent thing.
3. a pharmaceutical composition that is used for the treatment of and/or prevents hyperglycemia, high blood ester, hypertension, cardiovascular disorder or some drinking and eating irregularly comprises formula I compound, or its tautomeric forms, or all salt of its medicine, or its medicinal solvent thing, and pharmaceutical carrier.
4. the compound of claim 1 is used for the treatment of or prevents application in the medicine of hyperglycemia, high blood ester, cardiovascular disorder or some drinking and eating irregularly of human Mammals or non-human mammal in preparation.
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